The Merck Institute antimalarial compound, M5717, is the first plasmodium eEF2 inhibitor to reach clinical development, and is a good example of an orally available dibasic compound as well as an antimalarial with a discrete target identified after traditional phenotypic screening. It was well-tolerated in healthy volunteers and has a [...]

The Novartis RET inhibitor, compound 1, demonstrated robust oral in vivo efficacy in RET-driven tumor xenografts at low doses (10 mpk QD). RET inhibitors (selpercatinib and pralsetinib) have recently been approved in RET+ cancers based on significant efficacy in selected patients. Compound 1 was advanced through preclinical studies [...]

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The Genentech XIAP E3-ligase degrader, compound 10 , has an interesting mechanism of action, triggering the degradation of its target (XIAP) by ubiquitylation of the small molecule. The molecule behaves as a lysine mimetic, accepting ubiquitin from the targeted E3 complex, promoting XIAP’s own degradation. As E3 ligases are often difficult to [...]

The Vincerx Pharma/Bayer CDK9 inhibitor, VIP152 (BAY 1251152) , is a once-weekly (5-30 mg) IV agent in Ph. I for cancer with >50x family-selectivity . The sulfoximine-containing molecule is derived from the oral candidate atuveciclib (interestingly with opposite sulfoximine stereochemistry) and is significantly more potent under high ATP [...]

The Takeda GPR139 agonist, TAK-041 , is a CNS-penetrant GPCR agonist being explored for schizophrenia symptoms and is an interesting example of a triazinone-containing clinical candidate. GPR139 is an orphan GPCR that’s highly expressed in the human habenula, which plays a major role in avoidance behavior. Lesions in the habenula cause [...]

The Takeda AMPA-R potentiator, TAK-653 , is a glutamate-dependent potentiator that exhibits minimal agonism. AMPA-R agonism is associated with seizure risk and bell-shaped dose-response effects. As reviewer Jake Schwarz notes, companies including Cortex Pharmaceuticals (now RespireRx) and Lilly have been trying to develop AMPA modulators for [...]

The Incyte FGFR1/2/3 kinase inhibitor, pemigatinib , is an oral kinase inhibitor that obtained an FDA accelerated approval in 2020 for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma (bile duct cancer) with FGFR2 fusion or other rearrangement as detected by an FDA-approved test. There were no [...]

The Genentech next generation oral SERD (selective estrogen receptor degrader) and full antagonist, giredestrant (GDC-9545) , is a potential best-in-class Ph. III candidate for ER+, HER2- breast cancer (NCT04546009). It is the third SERD clinical candidate from Genentech (after GDC-0810 and GDC-0927) and a number of oral SERDs have previously [...]

The Altos Therapeutics /Takeda D2/D3 receptor antagonist, TAK-906 , is a peripherally-restricted, non-BBB penetrant molecule, targeting the stomach and vomiting center in the area postrema to treat gastroparesis. Gastroparesis is a chronic condition characterized by delayed gastric emptying, resulting in nausea, vomiting, pain, and anorexia [...]

The Takeda brain-penetrant M1R positive allosteric modulator (PAM), TAK-071, was optimized for lower cooperativity (α) with the native ligand to theoretically reduce the side effect of diarrhea from M1R activation. In animal models, higher cooperativity on M1R was associated with diarrhea, while lower cooperativity led to a wider margin. In [...]

The Janssen gut-restricted COX-2 inhibitor, compound 10 , is a tool compound used to test the hypothesis that gut-restricted COX-2 inhibition would be beneficial for cancer without the cardiovascular risk of systemic COX-2 inhibition. Unfortunately, IVIVC of several compounds demonstrated that in vivo efficacy was not driven by gut COX-2 [...]

The Kezar Life Sciences covalent immunoproteasome inhibitor, KZR-616 , licensed from Onyx , targets the LMP7 and LMP2 active sites of the immunoproteasome, and is currently in Ph. II trials for autoimmune disorders (30 mg SC QW for 2 weeks, then 45 mg SC weekly for 14 weeks). More subunit-selective, proteasome-sparing reversible-covalent LMP7 [...]

The PTC Therapeutics oral, brain-penetrant tubulin-binding agent, PTC596 , is in Ph. I clinical studies for advanced solid tumors (starting dose of 200 mg PO BIW). We recently highlighted encequidar , a P-gp inhibitor co-dosed with paclitaxel to render paclitaxel orally bioavailable. A directly orally bioavailable tubulin-binder would [...]

The AstraZeneca ATR serine/threonine kinase inhibitor, ceralasertib (AZD6738) , is a potent (1 nM biochemical IC50), orally bioavailable, ATP-competitive inhibitor, and is one of the most clinically advanced sulfoximines with ~32 registered clinical studies. An indole to azaindole change was key to mitigating CYP TDI during discovery, which [...]

The GSK BET BD2 inhibitor, GSK852 , is one of a series of BD2-targeting compounds published last month by GSK (see a fragment-based approach here , a DEL screening approach here , and a pincolinamide molecule here ). Each of these campaigns is impressive and educational in different ways, and the collective GSK BD2 effort is a tour de force [...]

The BMS AAK1 kinase inhibitor, compound 59 , is brain-penetrant and acts on the CNS. The target was identified from a phenotypic screen of mouse knockouts, and a non-brain penetrant inhibitor doesn’t show in vivo activity, confirming the central activity needed on the target. Targeting a kinase in the CNS for pain is bold due to the high bar [...]

The Cytokinetics second generation troponin activator, reldesemtiv , is intended to treat muscle weakness by directly activating skeletal muscle. A high concentration of free drug is expected to be needed due to the large amount of fast skeletal muscle troponin in the body, making safety and selectivity critical. Reldesemtiv demonstrated [...]