The Bayer DNA-PK inhibitor, BAY-8400 , is an orally active and selective DNA-PK kinase inhibitor that synergistically enhances the efficacy of radiotherapeutics in xenograft models. The program started with a campaign to identify ATR inhibitors, which resulted in hits against ATR, ATM, and DNA-PK, all of which are of interest due to their [...]

The Xenon NaV1.6 Inhibitor, NBI-921352 , is remarkably selective for the NaV1.6 sodium channel over other isoforms (IC50 = 51 nM, 756x vs. NaV1.1, 134X vs. NaV1.2, 276X vs. NaV1.7, >583X vs. 1.3, 1.4, 1.5). The molecule is It is being developed to treat pediatric patients with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and [...]

The Takeda covalent BTK inhibitor clinical candidate, TAK-020 , is a highly selective oral covalent BTK inhibitor with safety and tolerability profiles that are promising for both hematologic malignancies and autoimmune diseases based on a study in healthy volunteers. The molecule originated from a simple triazolone fragment, and overall is a [...]

The AstraZeneca oral RORgt inverse agonist, AZD0284 , is an inverse agonist of the nuclear receptor RORC2 (RORγt). Reviewer Chris Gampe says, “targeting the activation and function of Th17 cells has been successful for the treatment of autoimmune disease (cf. IL-17, IL-17R, IL-23 Abs). RORC2 is the transcription factor that controls Th17 [...]

The Merck KGaA MCT4 chemical probe, “compound 18n” , is a novel inhibitor of the monocarboxylate transporter MCT4. Large quantities of lactic acid need to be transported out of tumor cells due to their dependence on glucose metabolism, and this transport is mediated by MCTs. Overexpression of MCT4 is a marker for poor prognosis in cancer, and [...]

The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353) , was recently approved as the first non-steroidal treatment for prevention of hereditary angioedema attacks. The molecule is given orally (150 mg QD) despite having two basic amines (dibasic). Interestingly for a chronically administered drug, the molecule is noted to have [...]

The Celgene/BMS PKCθ kinase inhibitor, CC-90005 , highlighted by Julien Lefranc , is a clinical candidate in Ph. I for psoriasis, with some dosing being conducted in healthy volunteers. The safety profile is impressive given how fraught with selectivity issues previous PKC inhibitors have been. The molecule is >550-fold selective for PKCθ [...]

The Astex ERK1/2 kinase inhibitor, ASTX029 , is an oral Ph. I-II candidate for patients with advanced solid tumors. The molecule was derived from fragment screening together with structure-based design. Interestingly, the molecule also blocks the phosphorylation/activation of ERK1/2 in addition to inhibiting its kinase activity, making it [...]

The Takeda cholesterol 24-hydroxylase inhibitor, soticlestat (TAK-935, previously OV935) is a potent, highly selective, first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). Cholesterol 24-hydroxylase converts cholesterol to 24S-hydroxycholesterol, which acts as a positive allosteric modulator of [...]

The BMS spirocyclobutene-containing FXR agonist, BMS-986318 , appears to have been intended as a clinical candidate, but was withdrawn from a planned Ph. I study. The molecule exhibits potent in vitro and in vivo activation of FXR (FXR Gal4 reporter EC50 = 53 nM, SRC-1 recruitment assay EC50 = 350 nM) and demonstrates efficacy in the mouse [...]

The Takeda MAGL inhibitor, “compound 4f” , was selected by reviewer Joachim Rudolph . “MAGL (monoacylglycerol lipase) is implicated in neuroinflammation, and inhibitors of this enzyme are of interest as therapeutics in neurodegenerative and other neurological diseases. Most of the advanced compounds, including the clinically evaluated [...]

The Merck CETP inhibitor backup, MK-8262 , is potential best-in-class CETP inhibitor, which was only discontinued as a backup due to the success of its predecessor, anacetrapib in Ph. III. Reviewer Kim Huard thought this CETP inhibitor was a great piece of work from Merck, and is a great example how to deal with a very lipophilic binding site [...]

The Zentalis Wee1 inhibitor, ZN-c3 , is a highly selective kinase inhibitor that is currently being evaluated in Ph. II clinical trials in adult women with recurrent or persistent uterine serous carcinoma (USC). The starting pyrazolopyrimidinone series was from the WO2013126656 patent, and while the molecule is similar to other kinase [...]

The H3 Biomedicine RNA splicing modulator, H3B-8800, targets the spliceosome SF3b complex containing either wild-type (WT) or mutant SF3B1. Splicesome inhibition can induce synthetic lethality since cancer cells bearing spliceosome mutations are more dependent on WT spliceosome function. The compound is derived from the natural product [...]

The Minoryx peroxisome proliferator-activated receptor gamma (PPARγ) agonist, leriglitazone, is one of the several metabolites of pioglitazone, a member of the thiazolidinedione (glitazone) drug class for diabetes. It is instead being developed for a rare peroxisomal neurodegenerative disease, X-linked adrenoleukodystrophy (X-ALD). It [...]

The Chiesi M3 antagonist/PDE4 inhibitor dual pharmacology molecule, compound 92a, is an inhaled compound intended for pulmonary diseases. Both M3 and PDE4 are clinically validated targets for COPD (e.g. ipratropium and roflumilast). Dual pharmacology was thought to be valuable over two independent inhibitors in part due to the potentially [...]

The University of Michigan menin-MLL inhibitor, M-1121, is a covalent protein-protein interaction inhibitor that is orally active and achieves complete tumor regression in a xenograft model (300 mpk PO QD). MLL gene fusions are drivers of leukemias via interaction with menin, and small molecule menin-MLL inhibitors have shown preliminary [...]

The Artios Pharma selective allosteric Polθ DNA polymerase inhibitor, ART558, induces synthetic lethality in BRCA-mutant cancer cells and enhances PARP inhibitor activity. Defects in the 53BP1/Shieldin complex (which cause PARPi resistance) result in sensitivity to Polθ inhibition. The molecule is orally active in a mouse xenograft model [...]