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We report the discovery of ARD-2051 as a potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 achieves DC50values of 0.6 nM and Dmax>90% in inducing AR protein degradation in both the LNCaP and VCaP prostate cancer cell lines, potently and effectively suppresses AR-regulated genes, and inhibits cancer cell growth. ARD-2051 achieves a good oral bioavailability and pharmacokinetic profile in mouse, rat, and dog. A single oral dose of ARD-2051 strongly reduces AR protein and suppresses AR-regulated gene expression in the VCaP xenograft tumor tissue in mice. Oral administration of ARD-2051 effectively inhibits VCaP tumor growth and causes no signs of toxicity in mice. ARD-2051 is a promising AR degrader for advanced preclinical development for the treatment of AR+ human cancers.

Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8being selected as a clinical candidate for acute treatment of migraine.

We report herein the discovery and extensive characterization of ARD-1676, a highly potent and orally efficacious PROTAC degrader of the androgen receptor (AR). ARD-1676 was designed using a new class of AR ligands and a novel cereblon ligand. It has DC50values of 0.1 and 1.1 nM in AR+ VCaP and LNCaP cell lines, respectively, and IC50values of 11.5 and 2.8 nM in VCaP and LNCaP cell lines, respectively. ARD-1676 effectively induces degradation of a broad panel of clinically relevant AR mutants. ARD-1676 has an oral bioavailability of 67, 44, 31, and 99% in mice, rats, dogs, and monkeys, respectively. Oral administration of ARD-1676 effectively reduces the level of AR protein in the VCaP tumor tissue in mice and inhibits tumor growth in the VCaP mouse xenograft tumor model without any sign of toxicity. ARD-1676 is a highly promising development candidate for the treatment of AR+ human prostate cancer.

CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (Ki= 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (Ki= 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [35S]guanosine 5′-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50= 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50= 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.

CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H₃ receptor (H₃R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H₃R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H₃R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³⁵S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H₃R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC₅₀ = 0.1 ± 0.003 mg/kg), and antagonism of the H₃R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED₅₀ = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H₃R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.

Glycine transporter (GlyT1) function is typically measured by radiolabeled glycine uptake using lysis methods or scintillation proximity assays (SPAs), which have limited throughput. This study shows the adaptation of the standard cell lysis method to a screening assay with improved throughput and assay characteristics. The assay takes advantage of the 384-well format, standard laboratory automation, and cryopreserved CHO-K1 cells stably overexpressing human GlyT1a transporter (CHO-K1/hGlyT1a) that were validated and banked in advance of screening. The assay was evaluated for the time course of glycine uptake, Km, Vmax, Z′ factor analysis, and IC50value determination with reference GlyT1 inhibitors. Screening of 118,000 compounds at 10 μM identified 4556 compounds (3.9%) as inhibitors. Positive compounds (>50% inhibition) were retested in the assay at 4 inhibitor concentrations. Compounds demonstrating greater than 40% inhibition at 10 μM were considered as confirmed positives, yielding a 68% confirmation rate from the original screen. To eliminate compounds that nonspecifically inhibited glycine uptake, IC50values were determined in both GlyT1 and GlyT2 assays, and those compounds that inhibited GlyT2 were removed from consideration. The screening campaign identified 300 small molecules as selective GlyT1 inhibitors for lead optimization, demonstrating the utility of this cost-effective method.

The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)–derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)–independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK-leukemia cell line. ALK inhibition resulted in cell-cycle G1arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis.

The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)–derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)–independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis.

A series of potent P′-extended α-ketoamide inhibitors of chymotrypsin-like activity of proteasome is described.

We have developed a sensitive and continuously recording fluorogenic assay for the thiol protease calpain. This assay uses the dipeptide substrate Suc-Leu-Tyr-4-Methoxy-2-Naphthylamine (Suc-LY-MNA) in Tris buffer (pH 7.5) in the presence of 0.1% CHAPS. The assay is linear over a wide range of enzyme concentration and is capable of detecting 10 picomolar calpain making it more sensitive than any previously published method. Moreover, this assay gives a rate that is linear for over ten minutes making it useful for mechanistic studies of inhibitors. This assay can be easily adapted to a 96-well plate format facilitating the large scale screening of inhibitors.

Janus kinase 2 (JAK2) is involved in the downstream activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), including interleukin (IL)-6, interferon γ (IFNγ) and IL-12. In this paper, we describe the efficacy profile of CEP-33779, a highly selective, orally active, small-molecule inhibitor of JAK2 evaluated in two mouse models of RA.

This overview unit describes the core activities involved in the drug discovery and development process, from target identification ‐ including preclinical biology, medicinal and process chemistry ‐ to pharmacokinetics and metabolism (ADME), and also activities related to the to the drug approval process. The latter include the activities related to the filing of an IND (Investigational New Drug) application and also Phases I – III of clinical trials that form the basis of an NDA (New Drug Application) submission, as well as post‐marketing Phase IV activities as required by the U.S. Food and Drug Administration (FDA) and the European and Japanese counterparts

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Anaplastic large cell lymphomas (ALCLs) are a unique subgroup of high grade non-Hodgkin lymphomas. Approximately 60% to 70% of ALCLs contain a t (2:5) (p23; q35) chromosomal rearrangement, generating the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein. NPM-ALK encodes a constitutively activated tyrosine kinase that has been demonstrated to be directly involved in the pathogenesis of ALCLs. Currently there is no optimal therapeutic regimen for ALK positive ALCLs. Even with high dose CHOP (cyclophophamide, doxorubicin, vincristine and prednisone)-based chemotherapy, a substantial number of patients with ALK positive ALCLs have very poor outcome, either failing to enter remission or relapsing within a few months from the start of treatment. This prompted a search for small molecule ALK inhibitors as potential therapeutic agents for these patients. In this report, we describe the identification and characterization of a potent small molecule ALK inhibitor, cmpd-1. Cmpd-1 inhibited the ALK kinase activity in an in vitro enzymatic assay with an IC50 value of 4 nM. In NPM-ALK transfected BaF3 cells and ALCL-derived cell lines, cmpd-1 potently inhibited the tyrosine phosphorylation of NPM-ALK with a cellular IC50 value of 10–30 nM. Treatment with cmpd-1 inhibited IL-3 independent proliferation of BaF3 cells expressing constitutively active NPM-ALK (more than 95% inhibition at 100 nM) and the addition of IL-3 rescued the growth of these cells, while cmpd-1 had little effect on the parental BaF3 cells. Inhibition of NPM-ALK activity by cmpd-1 in ALK positive ALCL-derived cell lines, Karpas-299, Sudhl-1, Sup-M2 and Sr-786, resulted in inhibition of cell proliferation (50–90% inhibition at 100–300 nM) and induction of apoptotic cell death, while having marginal effects on the proliferation and survival of K562, an ALK negative leukemia cell line. These data suggest that the inhibition of cell proliferation and induction of apoptosis by cmpd-1 is an ALK-dependent event. Several putative downstream targets of NPM-ALK, including ERK1/2, Stat3 and Akt, were hypo- or unphosphorylated when the ALK positive cells were treated with cmpd-1. With the potent ALK inhibitory activity, cmpd-1 can be used as a molecular and pharmacological tool to study the biological roles of ALK and to dissect ALK-mediated signaling pathways in ALCLs and possibly other tumor types in which ALK is implicated in their pathogenesis.

Anaplastic large cell lymphomas (ALCLs) are a unique subgroup of high grade non-Hodgkin lymphomas. Approximately 60% to 70% of ALCLs contain a t (2:5) (p23; q35) chromosomal rearrangement, generating the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein. NPM-ALK encodes a constitutively activated tyrosine kinase that has been demonstrated to be directly involved in the pathogenesis of ALCLs. Currently there is no optimal therapeutic regimen for ALK positive ALCLs. Even with high dose CHOP (cyclophophamide, doxorubicin, vincristine and prednisone)-based chemotherapy, a substantial number of patients with ALK positive ALCLs have very poor outcome, either failing to enter remission or relapsing within a few months from the start of treatment. This prompted a search for small molecule ALK inhibitors as potential therapeutic agents for these patients. In this report, we describe the identification and characterization of a potent small molecule ALK inhibitor, cmpd-1. Cmpd-1 inhibited the ALK kinase activity in an in vitro enzymatic assay with an IC50value of 4 nM. In NPM-ALK transfected BaF3 cells and ALCL-derived cell lines, cmpd-1 potently inhibited the tyrosine phosphorylation of NPM-ALK with a cellular IC50value of 10–30 nM. Treatment with cmpd-1 inhibited IL-3 independent proliferation of BaF3 cells expressing constitutively active NPM-ALK (more than 95% inhibition at 100 nM) and the addition of IL-3 rescued the growth of these cells, while cmpd-1 had little effect on the parental BaF3 cells. Inhibition of NPM-ALK activity by cmpd-1 in ALK positive ALCL-derived cell lines, Karpas-299, Sudhl-1, Sup-M2 and Sr-786, resulted in inhibition of cell proliferation (50–90% inhibition at 100–300 nM) and induction of apoptotic cell death, while having marginal effects on the proliferation and survival of K562, an ALK negative leukemia cell line. These data suggest that the inhibition of cell proliferation and induction of apoptosis by cmpd-1 is an ALK-dependent event. Several putative downstream targets of NPM-ALK, including ERK1/2, Stat3 and Akt, were hypo- or unphosphorylated when the ALK positive cells were treated with cmpd-1. With the potent ALK inhibitory activity, cmpd-1 can be used as a molecular and pharmacological tool to study the biological roles of ALK and to dissect ALK-mediated signaling pathways in ALCLs and possibly other tumor types in which ALK is implicated in their pathogenesis.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.