Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.

Konteatis Z, Jin L, et al. ACS Med Chem Lett. 2020 Jan 22;11(2):101-107. doi: 10.1021/acsmedchemlett.9b00509. eCollection 2020 Feb 13.

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Programmed cell death 1 (PD-1) monoclonal antibodies have been approved by regulatory agencies for the treatment of various types of cancer, and the mechanism involves the restoration of T cell functions. We report herein the X-ray crystal structure of a fully human monoclonal antibody mAb059c fragment antigen-binding (Fab) in complex with the PD-1 extracellular domain (ECD) at a resolution of 1.70 Å. Structural analysis indicates 1) an epitope, comprising fragments from the C’D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C’D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact – ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds. Interface analysis reveals that N-glycosylation sites 49, 74 and 116 on PD-1 do not contact mAb059c; while N58 in the BC loop is recognized by mAb059c heavy chain CDR1 and CDR2. Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs.

Jingxian Liu, Guangqiang Wang, Lei Liu, Ruijuan Wang, Yi Wu, Chen Feng, Xiaohong Zhang, Jing Jiang, Ying Gu, He Zhou, Zhihong Xu, Zhiwei Sun, Dakang Chen, Wen Tian, Tian Yang, Ken Dai, Dexin Wang. Sci Rep. 2019 Nov 28;9(1):17830. doi: 10.1038/s41598-019-54231-w.

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Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).

Troxler T et al. ChemMedChem. 2019 Jul 3;14(13):1238-1247. doi: 10.1002/cmdc.201900176. Epub 2019 May 21.

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Bromodomain PHD finger transcription factor (BPTF), a bromodomain-containing protein, plays a crucial role in the regulation of downstream gene expression through the specific recognition of lysine acetylation on bulk histones. The dysfunction of BPTF is closely involved with the development and progression of many human diseases, especially cancer. Therefore, BPTF bromodomain has become a promising drug target for epigenetic cancer therapy. However, unlike BET family inhibitors, few BPTF bromodomain inhibitors have been reported. In this study, by integrating docking-based virtual screening with biochemical analysis, we discovered a novel selective BPTF bromodomain inhibitor DCB29 with the IC50 value of 13.2 ± 1.6 μM by homogenous time-resolved fluorescence resonance energy transfer (HTRF) assays. The binding between DCB29 and BPTF was confirmed by NMR and SPR. Molecular docking disclosed that DCB29 occupied the pocket of acetylated H4 peptide substrate and provided detailed SAR explanations for its derivatives. Collectively, DCB29 presented great potential as a powerful tool for BPTF-related biological research and further medicinal chemistry optimization.

Han J, Lu T, Zhang Y, et al. Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening. Bioorg Chem. 2019 May;86:494-500. doi: 10.1016/j.bioorg.2019.01.035. Epub 2019 Jan 28.

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The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is a promising therapeutic target for treatment of Th17 cell-mediated autoimmune diseases. Based on a scaffold hopping/conformational restriction strategy, a series of N-indanyl benzamides as novel RORγt inverse agonists was discovered. Exploration of structure-activity relationship on the piperazine ring, benzoyl moiety and cyclopentyl moiety of N-indanyl benzamides 2a and 2d led to identification of potent RORγt inverse agonists. Compound 5c with (S)-enantiomer was found having an IC50 of 153.7 nM in Fluorescence Resonance Energy Transfer (FRET) assay, and an IC50 of 47.1 nM in mouse Th17 cell differentiation assay, which represents a promising starting point for developing potent small molecule RORγt inverse agonists. Binding modes of the two enantiomers 5c and 5d in RORγt ligand binding domain were also discussed.

Jin Liu, Li Liu, et al. Eur J Med Chem. 2019 Apr 1;167:37-48. doi: 10.1016/j.ejmech.2019.01.082. Epub 2019 Feb 4.

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Proprotein convertase (PC) subtilisin kexin type 9 (PCSK9) inhibits the clearance of low density lipoprotein (LDL) cholesterol from plasma by directly interacting with the LDL receptor (LDLR). As the interaction promotes elevated plasma LDL cholesterol levels and a predisposition to cardiovascular disease (CVD), it has attracted much interest as a therapeutic target. While anti-PCSK9 monoclonal antibodies have been successful in the treatment of hypercholesteremia by decreasing CVD risk, their high cost and a requirement for injection have prohibited widespread use. The advent of an orally bioavailable small molecule inhibitor of the PCSK9-LDLR interaction is an attractive alternative, however efforts have been tempered as the binding interface is unfavourable for binding by small organic molecules. Despite its challenging nature, we report herein the discovery of compound 3f as a small molecule inhibitor of PCSK9. The kinase inhibitor nilotinib emerged from a computational screen that was applied to identify compounds that may bind to a cryptic groove within PCSK9 and proximal to the LDLR-binding interface. A subsequent in vitro PCSK9-LDLR binding assay established that nilotinib was a bona fide but modest inhibitor of the interaction (IC50 = 9.8 µM). Through multiple rounds of medicinal chemistry, 3f emerged as a lead-like molecule by demonstrating disruption of the PCSK9-LDLR interaction at nanomolar levels in vitro (IC50 = 537 nM) with no inhibitory activity (IC50 > 10 µM) against a small panel of kinases. Compound 3f restored LDL uptake by liver cells at sub-micromolar levels and demonstrated excellent bioavailability when delivered subcutaneously in mice. Most significantly, compound 3f lowered total cholesterol levels in the plasma of wild-type mice, thereby providing proof-of-concept that the notion of a small molecule inhibitor against PCSK9 is therapeutically viable.

Benny J Evison et al. Bioorg Med Chem. 2020 Mar 15;28(6):115344. doi: 10.1016/j.bmc.2020.115344. Epub 2020 Jan 31.

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Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key regulating effects in insulin signaling and leptin receptor pathways. In this work, a series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared and their PTP1B inhibitory potency, selectivity and membrane permeability were evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited remarkable inhibitory activity, significant selectivity as well as good membrane permeability (e.g. compound 28a, IC50 = 120, 1940 and 2670 nM against PTP1B, TCPTP and SHP2 respectively, and P app = 1.74 × 10 -6 cm/s). Molecular simulations indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger binding affinity than their cis-isomers by constructing more interactions with non-catalytic sites of PTP1B. Further biological activity studies revealed that compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated insulin receptor β (IRβ) phosphorylation with no significant cytotoxicity.

Xie F, Yang F, Zhang Y, Xia Y, Liu W, Jiang F, Lam C, Qiao Y, Xie D, Li J, Fu L. Investigation of stereoisomeric bisarylethenesulfonic acid esters for discovering potent and selective PTP1B inhibitors. Eur J Med Chem. 2019 Feb 15;164:408-422. doi: 10.1016/j.ejmech.2018.12.032. Epub 2018 Dec 14.

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The general control nonrepressed protein 5 (GCN5) is an important target for drug design and drug discovery largely owing to its pathogenic role in malignancies. Chemical probes that target GCN5 have been developed in recent decades, but their potencies are still unsatisfactory. In this study, through an in-house developed AlphaScreen-based high throughput screening platform, radioactive acetylation assays and 2D-similarity based analogue searching, we discovered DC_HG24-01 as the novel hGCN5 inhibitor with the IC50 value of 3.1 ± 0.2 μM. Further docking studies suggested that DC_HG24-01 could occupy the binding pocket of acetyl-CoA cofactor, which laid the foundation for the development of more potent hGCN5 inhibitors in the future. At the cellular level, DC_HG24-01 could retard cell proliferation of MV4-11 cell lines and block the acetylation of H3K14 leading to cell apoptosis and cell cycle arrest at the G1 phase. Taken together, the discovery of DC_HG24-01 may serve as a good starting point to accelerate the development of more potent hGCN5 inhibitors through further structural decoration and provide new insight into the pharmacological treatment of leukemia.

Tao H, et al. RSC Adv. 2019 Feb 8;9(9):4917-4924. doi: 10.1039/c8ra10074h.

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