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 [...]

The Merck protein arginine methyltransferase 5 (PRMT5) inhibitor (“compound 72”) is a SAM cofactor-mimetic with a novel 5,5-fused carbon-based bicyclic scaffold. PRMT5 is an actively pursued epigenetic target for cancer with a flurry of research programs being published recently and several trials being initiated. Remarkably, compound 72 has [...]

The Genentech transient receptor potential ankyrin 1 (TRPA1) inhibitor (“compound 20”) is an ion channel inhibitor with a binding site and mechanism of action characterized by cryo-EM. Structural information for ion-channel targets is rare as X-ray co-crystal structures of membrane-bound proteins are difficult to obtain. The article is an [...]

The Takeda lysine-specific demethylase 1 (LSD1) inhibitor (TAK-418) is an oral CNS-penetrant clinical candidate for neurodevelopmental disorders such as autism spectrum disorder. We previously highlighted irreversible and reversible LSD1 inhibitors intended to treat cancer. This tranylcypromine-derived clinical candidate is interesting [...]

The GlaxoSmithKline (GSK) Z α1-antitrypsin stabilizer (“compound 13,” GSK716) acts by blocking the formation of polymers within the endoplasmic reticulum of hepatocytes for treatment of α1-antitrypsin deficiency. It was identified through a DNA-encoded library screen with a nominal diversity of 2 trillion components. Compound 13 showed an [...]

The Galapagos-Servier selective ADAMTS-5 metalloproteinase inhibitor ( GLPG1972 ) recently completed a Ph. II study for knee osteoarthritis. Identification of small molecule clinical candidates for metalloproteinases is challenging due to selectivity issues and the chemical properties of needed metal-binding groups. The hydantoin is proposed [...]

The Bristol Myers Squibb apelin receptor (APJ) GPCR agonist ( “compound 14 ”) is a clinical candidate for heart failure which completed a Ph. I study. Endogenous pyroglutamated apelin-13 peptide has been shown to be beneficial in cardiovascular disease models, and this small molecule agonist was intended to treat heart failure by mimicking [...]

The Athenex/Hanmi Pharmaceutical P‑gp transporter inhibitor ( encequidar ) is a gut-restricted compound intended to reduce efflux and increase absorption of the IV drug, paclitaxel to enable oral paclitaxel delivery.  The use of transporter inhibitors in preclinical settings to improve drug exposure is well-established, and similar use in [...]

The Servier thrombin activatable fibrinolysis inhibitor (TAFIa) inhibitor ( S62798 ) is a fibrinolytic (clot degrading) agent which entered Ph. II in the EU for pulmonary embolism, but development appears to have been cancelled. TAFIa inhibitors are suggested to reduce clotting risk without  the risk of major hemorrhage since they don’t [...]

The Cerevance/Takeda GPR6 inverse agonist (CVN424) is an oral, once-daily clinical candidate in Ph. II for Parkinson’s disease after completing a Ph. I in healthy volunteers. Its >40 µM starting point was discovered through a 360k compound cell-based HTS targeting human GPR6 (an orphan GPCR). The molecule CVN424 is interesting because it is [...]

The AbbVie BCL-2 inhibitor prodrug (ABBV-167) is a phosphate prodrug of venetoclax used for treatment of chronic lymphocytic leukemia (CLL). This molecule has an interesting prodrug mechanism, masking an azaindole heterocycle through heterocycle N-alkylation. By improving the solubility, the dose needed of this prodrug relative to parent was [...]

The Genentech Nav1.7 inhibitor (GDC-0310) is a oral Ph. I clinical candidate for pain. Nav1.7 has been a hot target for pain, and we previously highlighted a Nav1.7 inhibitor as one of 2020’s Small Molecules of the Year. It is interesting among Nav1.7 inhibitors due to the presence of a very polar amine group where highly lipophilic elements [...]

The JNJ AR antagonist, JNJ-63576253, is a clinical molecule for prostate cancer that is active against both wild-type androgen receptor as well as the clinically relevant AR mutant, F877L. F887L is a devious resistance mechanism that transforms antagonists of AR into agonists. The parent compound from which 6253 is derived was found to be [...]

The Henan EGFR inhibitor, dosimertinib, is a deuterated derivative of the approved covalent inhibitor, osimertinib. A metabolite of osimertinib, AZ5104, has lower selectivity for WT EGFR than mutant EGFR, which the authors suggest may contribute to some adverse events. Deuteration of osimertinib appears to reduce the formation of the [...]

The BMS IDO1 inhibitor, BMS-986242, is a clinical candidate in a Ph. I/II study in combination with nivolumab for cancer. Like me, you probably had to look twice at this molecule since it’s so similar to linrodostat, which we covered recently. Forming the reverse amide of linrodostat appears to improve the PK profile and also removes a [...]

The CellCentric p300/CBP inhibitor, CCS1477, is an orally available drug in early development for advanced prostate cancer, and is structurally distinct from the p300/CBP inhibitor we covered in Apr. 2020. In agreement with its proposed MoA, it impacts AR and MYC signaling in serial tumor biopsies acquired from its first-in-human Ph. I trial. [...]

The Kissei SGLT2 inhibitor prodrug, remogliflozin etabonate , is an SGLT1-sparing oral drug launched in 2019 in India for the treatment of type 2 diabetes.  Interestingly, the lead for this drug was a metabolite identified from mouse urine after treatment with a Wyeth-Ayerst antihyperglycemic agent of previously unknown mechanism.

The Galapagos CFTR potentiator, GLPG2451, is an oral, once-daily clinical candidate for cystic fibrosis (5-80 mg QD). It was advanced into a high-profile Ph. II triple-combo study with the CFTR correctors GLPG2737 and GLPG2222 in partnership with AbbVie, and was seen as a potential competitor to Vertex’s CF franchise, but unfortunately weak [...]