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Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies. [ABSTRACT FROM AUTHOR]

Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC50 = 0.003 μM), KDR (IC50 = 0.032 μM), and several kinases involved in the MAPK signal transduction. This compound showed potent anti-TNBC activities both in vitro and in vivo, and good pharmacokinetic properties and low toxicity. Mechanisms of action of anti-TNBC were also investigated. Collectively, the data obtained in this study indicate that 13an could be a promising drug candidate for the treatment of TNBC and hence merits further studies. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment. [ABSTRACT FROM AUTHOR]

A seriesof 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure–activityrelationship (SAR) analysis of these compounds led to the discoveryof compound 1j, which showed the highest inhibitory potencyagainst the Src kinase and the most potent antiviability activityagainst the typical TNBC cell line MDA-MB-231 among all the synthesizedcompounds. Further kinase inhibition assays showed that compound 1jwas a multikinase inhibitor and potently inhibited Src(IC50= 0.0009 μM) and MAPK signaling protein kinasesB-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-dailydose of compound 1jat 30 mg/kg for 18 days completelysuppressed the tumor growth with a tumor inhibition rate larger than100% without obvious toxicity. It also displayed good pharmacokineticproperties in a preliminary pharmacokinetic assay. Western blot andimmunohistochemical assays revealed that compound 1jsignificantlyinhibited Src and MAPK signaling and markedly induced apoptosis intumor tissues. [ABSTRACT FROM AUTHOR]

Thedesign, synthesis, and SAR studies of novel inhibitors of HCVNS4B based on the imidazo[2,1-b]thiazole scaffoldwere described. Optimization of potency with respect to genotype 1bresulted in the discovery of two potent leads 26f(EC50= 16 nM) and 28g(EC50= 31 nM).The resistance profile studies revealed that 26fand 28gtargeted HCV NS4B, more precisely the second amphipathicα helix of NS4B (4BAH2). Cross-resistance between our 4BAH2inhibitors and other direct-acting antiviral agents targeting NS3/4A,NS5A, and NS5B was not observed. For the first time, the synergismof a series of combinations based on 4BAH2 inhibitors was evaluated.The results demonstrated that our 4BAH2 inhibitor 26fwas synergistic with NS3/4A inhibitor simeprevir, NS5A inhibitordaclatasvir, and NS5B inhibitor sofosbuvir, and it could also reducethe dose of these drugs at almost all effect levels. Our study suggestedthat favorable effects could be achieved by combining 4BAH2 inhibitorssuch as 26fwith these approved drugs and that new all-oralantiviral combinations based on 4BAH2 inhibitors were worth developingto supplement or even replace current treatment regimens for curingHCV infection. [ABSTRACT FROM AUTHOR]

Wedescribe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea(1), which exhibits inhibitory activity but low potencyagainst FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure–activityrelationship analysis using cell- and transgenic-zebrafish-based assaysled to the discovery of a number of compounds that exhibited bothhigh potency against FLT3-driven human acute myeloid leukemia (AML)MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-basedassays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin −4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea(33), which exhibited the highest activity in preliminaryin vivo anti-AML assays, was chosen for further anti-AML studies.The results demonstrated that compound 33is a multikinaseinhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograftmouse model, a once-daily dose of compound 33at 10 mg/kgfor 18 days led to complete tumor regression without obvious toxicity.Western blot and immunohistochemical analyses were performed to determinethe mechanism of action of compound 33. [ABSTRACT FROM AUTHOR]

This paper describe the structural optimization of ahit compound, N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine(1), which is a reversible kinase inhibitor targetingboth EGFR-activating and drug-resistance (T790M) mutations but haspoor binding affinity. Structure–activity relationship studiesled to the identification of 9-cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against thenon-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, whichharbor EGFR-activating and drug-resistance mutations, respectively.Compound 9ewas further assessed for potency and selectivityin enzymatic assays and in vivo anti-NSCLC studies. The results indicatedthat compound 9eis a highly potent kinase inhibitoragainst both EGFR-activating and resistance mutations and has goodkinase spectrum selectivity across the kinome. In vivo, oral administrationof compound 9eat a dose of 5 mg/kg caused rapid andcomplete tumor regression in a HCC827 xenograft model, and an oraldose of 50 mg/kg initiated a considerable antitumor effect in an H1975xenograft model. [ABSTRACT FROM AUTHOR]

Structure–activity relationship (SAR) studiesof 2-(quinazolin-4-ylthio)thiazolederivatives, which are for optimizing the in vitroand in vivoantiacute myeloid leukemia (AML) activityof a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole(1), are described. SAR studies centering around thehead (thiazole) and tails (6- and 7-positions) of the quinazolinemoiety of 1led to the discovery of a series of compoundsthat exhibited significantly increased potency against FLT3-drivenAML MV4-11 cells. Preliminary in vivoassays werecarried out on three highly active compounds, whose results showedthat 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest invivoactivity. Further in vitroand in vivoanti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20cat 100 mg/kg for 18 days led to complete tumor regressionwithout obvious toxicity. Western blot and immunohistochemical analysiswere carried out to illustrate the mechanism of action of 20c. [ABSTRACT FROM AUTHOR]