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Structures and PC3 viability IC50 data for compounds in Figure 2.

Supplementary methods, tables S1-S3, and supplementary figures 1-7

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45. ©2017 AACR.

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.

A series of substituted thienopyridine ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 2, are potent inhibitors of KDR (

A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).

Histone deacetylase inhibitors have generated significant interest as anti-cancer agents due to their ability to cause growth arrest, terminal differentiation and/ or apoptosis in carcinoma cells. Abbott entered this area after the serendipitous discovery of the biaryl hydroxamate A-161906 in a TGF beta mimetic screen and the subsequent identification of this compound as an inhibitor of selected HDACs. The complex biology of these enzymes became evident when cloning and expression of the HDACs demonstrated that they were present as multiprotein and, in some cases, multi-HDAC containing complexes in their active forms. This discovery suggested that any selectivity determinations would have to be considered in the context of these multi-protein/HDAC complexes. However, siRNA gene knockdown studies did demonstrate that reduction of the Class I HDACs resulted in a phenotype similar to that observed with small molecule HDAC inhibitors. Evaluation of the Abbott small molecule HDAC inhibitors utilized a Class I HDAC (HDAC 1/2) preparation and antiproliferation assays using HT1080 fibrosarcoma and MDA435 breast carcinoma cells. Characterization of several series of hydroxamic acids indicated that while many of these analogs possessed potent enzymatic and cellular activity, in general these compounds had unacceptable pharmacokinetic profiles and marginal antitumor effects. Replacement of the potentially labile hydroxamic acid moiety with a trifluoromethyl ketone or a ketooxazole gave measurable HDAC potency but only modest cellular and in vivo activity. However, hydroxamate replacement with an alpha-ketoamide moiety provided potent HDAC inhibitors (IC(50) values as low as 3 nM) with excellent cellular activity (IC50 values < 0.2 microM) and measurable anti-tumor activity in a flank tumor growth model.

Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition.

Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.

A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.

A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).

Excess MMP proteolytic activity has been associated with a wide variety of pathological conditions such as arthritis, cancer and heart failure. The potential utility of MMP inhibitors as therapeutic interventions in these diverse and important disease states has led to an intense effort toward the development of such inhibitors. The first generation of compounds were peptide-like broad spectrum inhibitors, active against a broad range of MMPs. However, the induction of musculoskeletal side effects seen in clinical trials with these agents has emphasized the need for a better understanding of the role that each of the MMPs plays in normal tissue turnover and disease progression. Advances in our ability to engineer and synthesize selective inhibitors as well as the discovery of small molecule, non-peptidic inhibitors has spurred an intense effort to identify potent and bioavailable second generation compounds. There are now several such compounds targeted against various subsets of the MMPs in clinical development. This review will focus on the design and structure activity relationships of these second generation compounds.

Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydrox-amic acids, some were found to be significant (IC50 < 1 μM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2′ amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or themolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.

Platelet activating factor (PAF) is an inflammatory mediator produced by a variety of cells in response to inflammatory and immune stimuli. It has been implicated in a wide range of pathological conditions such as septic shock, asthma, ischaemia/reperfusion injury, pancreatitis, inflammatory bowel disease and rhinitis. For this reason it has been postulated that an agent antagonising the action of PAF might have therapeutic value. Despite the longstanding effort of a number of pharmaceutical companies to bring a PAF antagonist to market and the fact that there are still a number of antagonists undergoing clinical trials in a variety of disease states, success in this field may not be realised in the near future. This review examines the PAF antagonist patent literature from 1995 to early 1998 with some discussion of the related literature articles. An attempt has been made to update the status of several older PAF antagonists that are or have been assessed in clinical trials.

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure−activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N,N-dimethylcarbamoyl)-4-ethynyl-3-{3-fluoro-4-[(1H-2-methylimidazo[4,5-c]pyrid-1-yl)methyl]benzoyl}indole hydrochloride (ABT-491, 22m·HCl) which has been evaluated extensively and is currently in clinical development.

A synthesis of the complete carbon skeleton of the nargenicins, represented by tricyclic lactone 45, is described. The key step of the synthesis of 45 is the Yamaguchi macrolactonization of hydroxy acid 44 which is followed by the facile transannular Diels−Alder reaction of the 18-membered macrolide 22. This sequence provides tricycle 45 in 66% yield, along with a 14% yield of tricycle 46 which is epimeric at C(10). Macrolide 22 was obtained in 38% yield when the macrolactonization was performed at 80 °C. The transannular Diels−Alder reaction of 22 at 80 °C provided tricycle 45 as the exclusive product (85% yield). In contrast, the intramolecular Diels−Alder reaction of seco ester 43 provided a mixture of trans-fused 47 in 56% yield and the desired cis-fused cycloadduct 48 in only 27% yield. Two independent stereochemical control features determine the success of the transannular Diels−Alder reaction of 22: the C(6)−Br steric directing group that dictates that only one of the two faces of the diene is ac...

3-(3-Pyridinyl)-7-(indol-3-ylcarbonyl)-1H-3H-pyrrolo[1,2-c]thiazoles represent a class of potent, orally active PAF antagonists; however, the lead compounds in this series suffered from a lack of aqueous solubility. To overcome this limitation, a number of strategies were examined to achieve improved solubility, involving the incorporation of polar substituents and the use of prodrugs.

New thienopyridine ureas (I) are potent inhibitors against the Aurora kinases that are efficacious in mouse tumor models after oral dosing.

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.

Rate studies have explored the effects of tether gem-dialkyl groups, allenyl substituents, fused ring size, and tether length on the intramolecular Diels-Alder reaction of vinylallenes. Additional new data on the «tert-butyl effect» has been provided. Mechanistic insight into the reaction has been developed which we hope will extend beyond the specific processes described herein. Finally, it has been further demonstrated that the IMDA reaction of vinylallenes is a versatile and convenient method to construct a wide range of polycycles

Excess MMP proteolytic activity has been associated with a wide variety of pathological conditions such as arthritis, cancer and heart failure. The potential utility of MMP inhibitors as therapeutic interventions in these diverse and important disease states has led to an intense effort toward the development of such inhibitors. The first generation of compounds were peptide-like broad spectrum inhibitors, active against a broad range of MMPs. However, the induction of musculoskeletal side effects seen in clinical trials with these agents has emphasized the need for a better understanding of the role that each of the MMPs plays in normal tissue turnover and disease progression. Advances in our ability to engineer and synthesize selective inhibitors as well as the discovery of small molecule, non-peptidic inhibitors has spurred an intense effort to identify potent and bioavailable second generation compounds. There are now several such compounds targeted against various subsets of the MMPs in clinical development. This review will focus on the design and structure activity relationships of these second generation compounds.

[14630-40-1] C8H18Si2 (MW 170.40) InChI = 1S/C8H18Si2/c1-9(2,3)7-8-10(4,5)6/h1-6H3 InChIKey = ZDWYFWIBTZJGOR-UHFFFAOYSA-N (nucleophile in Friedel–Crafts type acylations and alkylations; lithium trimethylsilylacetylide precursor; cycloaddition substrate) Alternate Name: BTMSA. Physical Data: mp 26 °C; bp 136–137 °C; d 0.752 g cm−3. Solubility: sol all commonly used organic solvents. Form Supplied in: clear liquid; widely available. Preparative Method: from acetylene by treatment with n-Butyllithium followed by Chlorotrimethylsilane.1 Handling, Storage, and Precautions: the liquid is flammable and an irritant. Use in a fume hood.

7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (

Rate studies have explored the effects of tether gem-dialkyl groups, allenyl substituents, fused ring size, and tether length on the intramolecular Diels-Alder reaction of vinylallenes. Additional new data on the «tert-butyl effect» has been provided. Mechanistic insight into the reaction has been developed which we hope will extend beyond the specific processes described herein. Finally, it has been further demonstrated that the IMDA reaction of vinylallenes is a versatile and convenient method to construct a wide range of polycycles

Reactions of thionyl chloride-dimethylformamide reagent at 58°C in deuteriochloroform with 1-triptycylcarbinol and ditriptycylcarbinol produced the sulfite ester and the interesting rearranged compound 1-chloro-2-(1-triptycyl) tribenzobicyclo [3.2.2] nonatriene (a triptycyl-substituted homotriptycene), respectively. The mechanistic differences that occur after initial formation of chlorosulfite intermediates are discussed. Molecular mechanics calculations were used to explore the exothermicity of this and related rearrangements

Histone deacetylases (HDACs) alter the acetylation status of chromatin and thereby effect gene expression. The inappropriate recruitment of HDACs may be one mechanism by which oncogenes can alter gene expression in favor of excessive cell proliferation, making inhibition of HDACs a potential target for the development of small-molecule anticancer agents. As a consequence there are several HDAC inhibitors currently undergoing clinical trials for the treatment of solid and non-solid tumors. This review examines recent synthetic methods used to prepare the diverse family of HDAC inhibitors, and includes syntheses of several of the current clinical candidates. The review is divided into the structural classes of known HDAC inhibitors, including non-peptidic hydroxamic acids, non-hydroxamate analogs and cyclic peptides.

Histone deacetylases (HDACs) alter the acetylation status of chromatin and thereby effect gene expression. The inappropriate recruitment of HDACs may be one mechanism by which oncogenes can alter gene expression in favor of excessive cell proliferation, making inhibition of HDACs a potential target for the development of small-molecule anticancer agents. As a consequence there are several HDAC inhibitors currently undergoing clinical trials for the treatment of solid and non-solid tumors. This review examines recent synthetic methods used to prepare the diverse family of HDAC inhibitors, and includes syntheses of several of the current clinical candidates. The review is divided into the structural classes of known HDAC inhibitors, including non-peptidic hydroxamic acids, non-hydroxamate analogs and cyclic peptides.

A series of structurally novel HDAC inhibitors, in which a hetero aromatic ring connects the spacer with the hydrophobic group, has been designed and synthesized. These new inhibitors are very potent in in vitro enzymatic assays and display antiproliferation activity against two human cancer cell lines.

Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.

Histone deacetylases (HDACs) are a family of enzymes involved in transcription regulation. HDACs are known to play key roles in the regulation of cell proliferation; consequently, inhibition of HDACs has become an interesting approach for anti-cancer therapy. However, expression of mammalian HDACs has proven to be difficult. All attempts to express these HDACs in E.coli, Pichia and baculovirus systems were unsuccessful. Here we present the stable expression of human recombinant His-tagged HDAC1 and HDAC3 in mammalian cells. Full-length human genes for HDAC1 and HDAC3 were cloned into the pcDNA 3.1 vector containing a N-terminal His-tag with an enterokinase cleavage site. Recombinant HDAC enzyme activity was only detected after nickel affinity purification due to high activity of endogenous HDACs; and removal of the His-tag increased activity 2-4 fold. Western blots demonstrated the nickel affinity purified rhHDAC1 preparation also contained endogenous HDAC2 and HDAC3; likewise, rhHDAC3 preparation contained endogenous HDAC1 and HDAC2. Therefore, the active HDAC preparation is actually a multi-protein and a multi-HDAC containing complex. This provides one explanation for the similar IC50 values exhibited by SAHA and MS-275 against nuclear HDACs and rhHDAC1 and 3 preparations. These results demonstrate that recombinant forms of the HDACs can be over-expressed in mammalian cells, isolated as active multi-protein complexes that contain multiple HDAC enzymes, and caution must be used when determining HDAC inhibitor in vitro selectivity.

A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (1nM), FTase/GGTase selective (300-fold) and cellularly active (or=80nM). An X-ray crystal structure of inhibitor 21 bound to rat farnesyltransferase is also presented.

Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.

(n-BuLi) [109-72-8] C4H9Li (MW 64.06) InChI = 1S/C4H9.Li/c1-3-4-2;/h1,3-4H2,2H3; InChIKey = MZRVEZGGRBJDDB-UHFFFAOYSA-N (BF3·OEt2) [109-63-7] C4H10BF3O (MW 141.93) InChI = 1S/C4H10O.BF3/c1-3-5-4-2;2-1(3)4/h3-4H2,1-2H3; InChIKey = KZMGYPLQYOPHEL-UHFFFAOYSA-N (Lewis acid catalyst/strong base combination used to simultaneously generate an anion and activate an electrophile at low temperature, i.e. double activation2) Physical Data: see n-Butyllithium and Boron Trifluoride Etherate. Form Supplied in: the reagents are mixed with reactants in situ. BF3·OEt2 is supplied as a purified, redistilled liquid. n-Butyllithium is available as a 2 M solution in cyclohexane, 1.6 M, 2.5 M, and 10 M solution in hexanes, and a 2 M solution in pentane. Handling, Storage, and Precautions: BF3·OEt2 is a fuming, corrosive liquid and is immediately hydrolyzed by moisture in air; n-butyllithium solutions are moisture sensitive and pyrophoric. Accordingly, both reagents should be stored and handled in the absence of moisture under N2.3

A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.

A series of P 1 C α gem-disubstituted succinamide hydroxamate matrix metalloproteinase inhibitors were prepared stereoselectively and evaluated in vitro for their ability to inhibit MMP-1, MMP-2, and MMP-3. It was found that while methyl/allyl substitution as in 2 and 18 provided compounds that were broad spectrum inhibitors and nearly equipotent with parent inhibitor 1 , a larger group such as bis-allyl as in 13 or gem-cyclopentyl as in 14 significantly reduced enzyme inhibition.

ABT-491 (4-ethynyl- N , N -dimethyl-3-[3-fluoro-4-[(2-methyl-1 H -imidazo-[4,5- c ]pyridin-1-yl)methyl]benzoyl]-1 H -indole-1-carboxamide hydrochloride) is a novel PAF (platelet-activating factor) receptor antagonist with a K i for inhibiting PAF binding to human platelets of 0.6 nM. Binding kinetics of ABT-491 to the PAF receptor is consistent with a relatively slow off-rate of the antagonist when compared to PAF. Inhibition of PAF binding is selective and is correlated with functional antagonism of PAF-mediated cellular responses (Ca 2+ mobilization, priming, and degranulation). Administration of ABT-491 in vivo leads to potent inhibition of PAF-induced inflammatory responses (increased vascular permeability, hypotension, and edema) and PAF-induced lethality. Oral potency (ED 50 ) was between 0.03 and 0.4 mg/kg in rat, mouse, and guinea-pig. When administered intravenously in these species, ABT-491 exhibited ED 50 values between 0.005 and 0.016 mg/kg. An oral dose of 0.5 mg/kg in rat provided >50% protection for 8 h against cutaneous PAF challenge. ABT-491 administered orally was also effective in inhibiting lipopolysaccharide-induced hypotension (ED 50 =0.04 mg/kg), gastrointestinal damage (0.05 mg/kg, 79% inhibition), and lethality (1 mg/kg, 85% vs. 57% survival). The potency of this novel antagonist suggests that ABT-491 will be useful in the treatment of PAF-mediated diseases. © 1997 Elsevier Science B.V.

ABT-348 is a novel, potent and orally bioavailable inhibitor of the Aurora kinases as well as the VEGF and PDGF families of receptor tyrosine kinases. ABT-348 is broadly efficacious preclinically as a single agent against a wide range of tumor types and is currently in Phase I/II clinical trials. Several published studies have supported the potential utility of combining targeted anti-proliferative agents with cytotoxic chemotherapies. Herein, the efficacy of combining the neocytotoxic agent, ABT-348, with CDK4/6 inhibition in the treatment of solid tumor cells has been evaluated. Inhibition of CDK4/6 via siRNA elicits a potent cytostatic response in cells that harbor a wild-type, functional RB. We demonstrate that features of cellular senescence are induced in human tumor cells with siRNAs targeting both CDK4 and CDK6. Dual inhibition of CDK4 and CDK6 is required for antiproliferative activity in most cancer cell lines and this is not accompanied by induction of apoptosis. In RB wild-type cells, CDK4/6 inhibition antagonizes the activity of ABT-348 by inducing G0/G1 arrest. Conversely, CDK4/6 inhibition does not alter the therapeutic response of RB-deficient cells to ABT-348, indicating that the effects of ABT-348 are dependent on cells progressing into mitosis. A preponderance of evidence from previous publications and our studies indicate that CDK4/6 inhibition attenuates the cellular response to cytotoxic chemotherapies in RB wild-type cells providing a potential to expand the therapeutic window for ABT-348. Thus combination with ABT-348 and a CDK4/6 inhibitor may provide an opportunity to selectively target RB mutant cells. Citation Format: Jun Guo, Michael L. Curtin, Zehan Chen, Daniel H. Albert, Paul Tapang, Yujia Dai, Mia-Ha Bui, Peter Kovar, Michael R. Michaelides, Keith B. Glaser, Chris Tse, O. Jameel Shah. ABT-348 in combination with inhibition of CDK4/6 highlights a strategy to target RB mutant cells while sparing RB wild-type cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3450. doi:10.1158/1538-7445.AM2013-3450

The Aurora kinases (Aurora A, B, and C) play essential roles in regulating cell division in mammalian cells and their over-expression in diverse tumor types makes them appealing oncology targets. ABT-348 is a novel, ATP-competitive, multi-targeted kinase inhibitor that exhibits potent activity in multiple solid tumor-derived and leukemia cell lines. ABT-348 is active against Aurora B (IC50 7 nM) and Aurora C (IC50 1 nM), Aurora A (IC50 120 nM). The activity against Aurora B is demonstrated by inhibition of histone H3 phosphorylation and induction of polyploidy. ABT-348 is also active against Aurora-B Y156H, a mutant resistant to other Aurora-B inhibitors. In addition, ABT-348 potently inhibits most members of the VEGFR and PDGFR family of receptor tyrosine kinases, which play a critical role in stromal angiogenesis. In contrast to other Aurora kinase inhibitors, the cellular efficacy of ABT-348 is retained in cells over-expressing P-glycoprotein (Pgp) or breast cancer resistant protein (BCRP), indicating that ABT-348 is not a substrate for these commonly upregulated ATP-binding cassette drug transporters. Consistent with these in vitro studies, ABT-348 was broadly efficacious as a single agent against a wide range of tumor types in vivo, including 3 multi-drug resistant xenograft models. In summary, the potent activity and unique kinase selectivity of ABT-348 against the Aurora kinases and VEGF and PDGF receptor tyrosine kinases, engender its ability to block multiple mechanisms of tumor progression. In addition, our data provide evidence that ABT-348 may be active in tumors resistant to other well-characterized inhibitors targeting Aurora-B. ABT-348 is presently under clinical evaluation in adult patients with advanced solid and hematological neoplasms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1818. doi:1538-7445.AM2012-1818