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Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3–5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development. Here we provided a series of DDR1/2 inhibitors with reliable in vivo anti-fibrosis efficacy, among which compound 47 was a promising candidate for further drug development. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC 50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1 H )-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 μM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) as a key negative regulator of both insulin and leptin receptor pathways has been an attractive therapeutic target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. With the goal of enhancing potency and selectivity of the PTP1B inhibitors, a series of methyl salicylate derivatives as ABC type PTP1B inhibitors ( P1–P7 ) were discovered. More importantly, compound P6 exhibited high potent inhibitory activity (IC 50 = 50 nM) for PTP1B with 15-fold selectivity over T-cell PTPase (TCPTP). Further studies on cellular activities revealed that compound P6 could enhance insulin-mediated insulin receptor β (IRβ) phosphorylation and insulin-stimulated glucose uptake. [ABSTRACT FROM AUTHOR]

The signal transduction of acetylatedhistone can be processedthrough a recognition module, bromodomain. Several inhibitors targetingBRD4, one of the bromodomain members, are in clinical trials as anticancerdrugs. Hereby, we report our efforts on discovery and optimizationof a new series of 2-thiazolidinones as BRD4 inhibitors along ourprevious study. In this work, guided by crystal structure analysis,we reversed the sulfonamide group and identified a new binding mode.A structure–activity relationship study on this new seriesled to several potent BRD4 inhibitors with IC50of about0.05–0.1 μM in FP binding assay and GI50of0.1–0.3 μM in cell based assays. To complete the lead-likeassessment of this series, we further checked its effects on BRD4downstream protein c-Myc, investigated its selectivity among fivedifferent bromodomain proteins, as well as the metabolic stabilitytest, and reinforced the utility of 2-thiazolidinone scaffold as BETbromodomain inhibitors in novel anticancer drug development. [ABSTRACT FROM AUTHOR]

Upregulation of pyruvate dehydrogenasekinase (PDHK) has been observedin a variety of cancers. Inhibition of PDHK offers an attractive opportunityfor the development of novel cancer therapies. To obtain novel PDHKinhibitors, we took advantage of the homology of the ATP-binding pocketbetween Heat Shock Protein 90 (HSP90) and PDHK, and utilized 4,5-diarylisoxazolebased HSP90 inhibitor for structural design. Our efforts led to theidentification of 5kthat inhibited PDHK1 with an IC50value of 17 nM, which, however, showed marginal cellularactivity. Further structural optimization resulted in compound 11awith improved cellular activity which could effectivelymodulate the metabolic profile of cancer cells and lead to the inhibitionof cancer cell proliferation, evidenced by the increased oxidativephosphorylation and decreased glycolysis and associated oxidativestress. Our results suggested 11aas an excellent leadcompound and a favorable biological tool to further evaluate the therapeuticpotential of PDHK and HSP90 dual inhibitors in the treatment of cancer. [ABSTRACT FROM AUTHOR]

HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N -(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide ( 108 ) showed high affinity for binding to HSP90 (FP binding assay, IC 50 = 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI 50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. [ABSTRACT FROM AUTHOR]

Abstract: Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20–40nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs. [Copyright &y& Elsevier]

Abstract: The potential roles of 11β-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11β-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl–oxadiazole derivatives as human 11β-HSD1 inhibitors, we explored the structure–activity relationship of several parts of the lead compound. Based on their potency toward human 11β-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11β-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model. [Copyright &y& Elsevier]

Abstract: The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5×6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20μg/mL, with IC50 values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html). [Copyright &y& Elsevier]

Abstract: The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB1 receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB1 receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague–Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure–activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed. [Copyright &y& Elsevier]