The Chinook LDHA/GO dual inhibitor, compound 7 , targets two clinically validated targets for hyperoxaluria, a rare genetic disorder that results in oxalate overproduction and sometimes kidney failure. GO is encoded by HAO1 , the target of recently approved siRNA drug lumasiran , and LDHA is selectively targeted by Dicerna’s nidosiran . The [...]

the X-Chem covalent BTK inhibitor, compound 6 , is an example of a covalent inhibitor discovered using DNA-encoded library chemistry, and is the first epoxide-based covalent inhibitor discovered against BTK. Screening for novel covalent scaffolds is challenging, and many covalent leads are instead discovered from reversible starting points [...]

The Revolution Medicines KRASG12C inhibitor, RM-018, “glues” KRASG12C to the highly abundant chaperone protein, cyclophilin A, in a tri-complex (KRAS- inhibitor-cyclophilin A) stabilized by protein-protein interactions. KRAS is a driver of cancer cell growth, and mutants including KRASG12C have been hot targets due to the newfound ability to [...]

The Genentech TRPA1 ion-channel inhibitor, GDC-0334, is an oral candidate for asthma that demonstrated target engagement in a non-invasive skin- based Ph. I study. It reduces TRPA1 agonist-induced symptoms in healthy volunteers, with near complete TRPA1 inhibition at 600 mg. TRPA1 is most well-known as a receptor activated by irritants such [...]

The Bayer soluble guanylate cyclase (sGC) activator, BAY 1101042 (runcaciguat), is a once-daily (50 mg), oral clinical candidate in Ph. II for chronic kidney disease and diabetic retinopathy. sGC is an intracellular receptor for nitric oxide (NO), binding NO via a heme-cofactor, which activates a catalytic domain that leads to production of [...]

The Agios first-in-class oral MAT2A enzyme allosteric inhibitor, AG-270, is a Ph. I clinical candidate for tumors with MTAP gene loss. The inhibitor works on a synthetic lethality principle: the MTAP -loss which drives tumors also makes them particularly sensitive to reduction in S - adenosyl methionine (SAM) levels, and since MAT2A is the [...]

The UC Berkeley and Novartis deubiquitinating enzyme-recruiting chimera (DUBTAC), NJH-2-057, has a warhead that covalently targets a non-catalytic allosteric cysteine on the deubiquitinase (DUB) OTUB1. The CFTR-binding moiety recruits OTUB1 to the mutant ion channel, ΔF508-CFTR, stabilizing the protein by preventing its polyubiquitination and [...]

The Roche GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, is a Ph. II candidate for intellectual disability in Down syndrome. GABAA receptors assemble as pentamers of subunits, and non- subunit selective compounds have anxiogenic or convulsive side effects. Basimasil is the only safe and selective GABAA-α5 inhibitor that [...]

The Storm Therapeutics/Cambridge METTL3 RNA methyltransferase inhibitor, STM-2457, is a first-in-class catalytic inhibitor of the METTL3 RNA modifying enzyme. DNA-methyltransferase and other epigenetic targets such as HDACs have been explored for their potential roles in cancer and other diseases, and this compound brings RNA modifying [...]

The AstraZeneca MAT2a allosteric inhibitor, compound 28, is a remarkably potent (25 nM in cells) in vivo tool compound generated from merging of two weak fragments (Kd = 250 μM and 6.2 μM). The molecule binds in the same site as AG-270 (above) and has a relatively uncommon quinazolinone core, which makes several polar interactions in the [...]

The Vivace Therapeutics pan-TEAD transcription factor inhibitor, VT-104, binds to a lipid pocket on TEAD, preventing its auto-palmitoylation, similar to a previously highlighted TEAD inhibitor. In contrast to previously published TEAD inhibitors, VT104 has high oral bioavailability (78%) and a long half-life (24 h) in mice, and demonstrates [...]

The Cleave Therapeutics p97 (VCP) inhibitor, CB-5083, was a Ph. I clinical candidate for cancer that was terminated due to vision side effects including causing patients to see unusual colors (dyschromatopsia). In this paper, the authors suggest that the visual impairment was due to the compounds inhibition of the phosphodiesterase-6 (PDE6) [...]

The Fuji Yakuhin FXR/TGR5 non-bile acid dual agonist, compound 20p, simultaneously activates the FXR nuclear receptor and the unrelated TGR5 GPCR receptor when dosed orally in vivo. FXR has been a important target for liver disease, and a number of agonists have been in development, including one of last year’s Molecules of the Year. TGR5 is [...]

The Eternity Bioscience/Shanghai Hengrui RORγ antagonist, SHR168442, is a skin-restricted, topical compound intended to treat psoriasis. As a master regulator of Th17 immune cells which are significantly involved in allergic diseases, both positive and negative oral modulators of RORγt had been hotly pursued, though many have ceased clinical [...]

The Genentech pan-RAF Type II kinase inhibitor, GNE-9815, is an oral chemical probe and among the most highly kinase-selective inhibitors of RAF reported. Interestingly, it minimally engages the hinge region of the kinase with a weak hydrogen bond acceptor and a polarized C-H···O=C hydrogen bond. Type I BRAF inhibitors targeting BRAFV600E [...]

The TSRI/UCSF/Lundbeck pan-ABHD17 serine hydrolase covalent inhibitor, ABD957, impairs N-Ras depalmitoylation in AML cells, reducing N-Ras signaling and growth of NRAS-mutant AML cells. This pyrazole urea is significantly more selective for ABHD17 than previously used beta-lactone and phosphonylfluoride tools, and helps clarify the biological [...]

The Reviral respiratory syncytial virus (RSV) fusion inhibitor (sisunatovir) is an oral Ph. II clinical candidate that demonstrated reduction in viral load and total symptom score in RSV-infected patients and has received the Fast Track designation from the FDA. Crowded areas for development such as for RSV often lead to interesting chemical [...]

The Ribon Therapeutics PARP14 inhibitor (RBN-012759) is a tool compound with >300x selectivity over all PARP family members. While PARP1/2 are well-known to drug hunters as synthetic lethal targets due to their role in DNA damage repair, there are 17 PARP enzymes with many other biological roles without as much pharmacological exploration [...]