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The histone methyltransferase EZH2 has been the target of numerous small-molecule inhibitor discovery efforts over the last 10+ years. Emerging clinical data have provided early evidence for single agent activity with acceptable safety profiles for first-generation inhibitors. We have developed kinetic methodologies for studying EZH2-inhibitor-binding kinetics that have allowed us to identify a unique structural modification that results in significant increases in the drug-target residence times of all EZH2 inhibitor scaffolds we have studied. The unexpected residence time enhancement bestowed by this modification has enabled us to create a series of second-generation EZH2 inhibitors with sub-pM binding affinities. We provide both biophysical evidence validating this sub-pM potency and biological evidence demonstrating the utility and relevance of such high-affinity interactions with EZH2., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Contemporary deep learning approaches still struggle to bring a useful improvement in the field of drug discovery because of the challenges of sparse, noisy, and heterogeneous data that are typically encountered in this context. We use a state-of-the-art deep learning method, Alchemite, to impute data from drug discovery projects, including multitarget biochemical activities, phenotypic activities in cell-based assays, and a variety of absorption, distribution, metabolism, and excretion (ADME) endpoints. The resulting model gives excellent predictions for activity and ADME endpoints, offering an average increase in R 2 of 0.22 versus quantitative structure-activity relationship methods. The model accuracy is robust to combining data across uncorrelated endpoints and projects with different chemical spaces, enabling a single model to be trained for all compounds and endpoints. We demonstrate improvements in accuracy on the latest chemistry and data when updating models with new data as an ongoing medicinal chemistry project progresses.

Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD cofactor of LSD1. The series was rapidly progressed to potent biochemical and cellular LSD1 inhibitors with good physical properties. This effort resulted in the identification of 34 , a highly potent (<4 nM biochemical, 2 nM cell, and 1 nM GI 50 ), and selective LSD1 inhibitor. In-depth kinetic profiling of 34 confirmed its covalent mechanism of action, validated the styrenylcyclopropane as an FAD-directed warhead, and demonstrated that the potency of this inhibitor is driven by improved non-covalent binding ( K I ). 34 demonstrated robust cell-killing activity in a panel of AML cell lines and robust antitumor activity in a Kasumi-1 xenograft model of AML when dosed orally at 1.5 mg/kg once daily., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17 , was developed from the lead compound 3 . Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1 R132H . This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG., Competing Interests: The authors declare the following competing financial interest(s): The authors are all current or former employees of Novartis and some own shares in Novartis.

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg 132 . Having identified an allosteric, induced pocket of IDH1 R132H , we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 ( 13 ), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 ( 13 ) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1 R132H . Synthesis of the four separate stereoisomers identified the ( S , S )-diastereomer ( IDH125 , 1f ) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1 wt . Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified ( S , S )-oxazolidinone IDH889 ( 5x ) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model., Competing Interests: The authors declare no competing financial interest.

4H-Substituted pyrylium 9, benzo[b]pyrylium 15, and xanthylium salts 22 react with benzotriazole to give the corresponding 4H-(benzotriazol-1-yl)pyrans 10, benzo[b]pyrans 16, or xanthenes 23. Novel anion precursors 10, 16, and 23 undergo smooth lithiations at the positions alpha to the benzotriazol-1-yl function, i.e., at the para-position of the O-heterocycle. Subsequent trapping with different alkyl halides gives intermediates 14, 21, and 25, which are converted by mineral acid into para-functionalized pyrylium 11-13, benzo[b]pyrylium 17-20, and the xanthylium 24 salts in good to excellent yields.