October’s Molecules of the Month include a small molecule that leverages induced proximity to activate mutant p53, along with Roche’s highly potent and selective MAGL inhibitor for CNS disorders. We also highlight two inhibitors of αvβ6, a key target for fibrotic diseases but linked to notable safety risks. Other featured molecules include an oral therapy for PKU with newly published Ph. III data and a long-acting injectable prodrug for malaria prevention.
You can read more about the compounds that made our October 2024 Molecules of the Month list and check out recent articles for each, linked below:
TRAP-1 – TRAP-1 (TRanscriptional Activator of p53) is a small molecule from Nathanael Gray’s lab at Stanford that leverages chemically induced proximity to activate mutant p53, a notoriously challenging target in cancer therapy. TRAP-1, which is structurally similar to PMV Pharma’s potential first-in-class p53 Y220C reactivator rezatapopt and the non-degrading bifunctional tool compound, PMV6-C3-BI2536, forms a ternary complex with mutant p53 and BRD4, leading to potent transcriptional activation of p53 target genes, including p21. In p53 Y220C-expressing pancreatic cancer cell lines, TRAP-1 induces rapid upregulation of p53-responsive genes and inhibits cell growth. Control compounds unable to form the ternary complex exhibit no such effects, underscoring the necessity of proximity-induced engagement for pharmacological activity.
EDI048 – A GI-targeted PI(4)K (phosphatidylinositol-4-OH kinase) inhibitor designed as an oral soft drug from Novartis to treat Cryptosporidium infections in children. It is stable in the gastrointestinal tract, where it exerts potent parasiticidal activity, and undergoes rapid hepatic metabolism to minimize systemic exposure. Preclinical studies in mouse and neonatal calf models demonstrate its efficacy in reducing parasite burden, resolving diarrhea, and preventing infection recrudescence, with negligible systemic concentrations and no apparent emergence of resistance. While primarily effective against enteric infections, its GI-targeted design minimizes systemic toxicity, making it an ideal candidate for pediatric use. Currently in Ph. I clinical trials (NCT05275855), EDI048 has the potential to address the critical unmet need for a safe and effective treatment for pediatric cryptosporidiosis.
compound (S)-20 – Developing orally bioavailable inhibitors of αvβ6, a critical target for treating fibrotic diseases, has been particularly challenging given that the common zwitterionic pharmacophore required for binding the RGD (arginyl-glycinyl-aspartic acid) site complicates drug design, and targeting integrins can lead to well-known safety risks given that they are upstream of TGF-β (transforming growth factor-β) leading to several high-profile αvβ6 inhibitors being terminated for safety concerns. Now GSK has disclosed the design and optimization of a new series of orally bioavailable αvβ6 inhibitors, leveraging their prior work on GSK3008348 and GSK3335103. To address the limitations of these first-generation inhibitors, GSK aimed to reduce the basicity of the central ring nitrogen in GSK3008348 while avoiding the synthetic complexity associated with the chiral, fluorine-containing quaternary carbon center of GSK3335103. Lead compound (S)-20 demonstrates potent αvβ6 inhibition, oral bioavailability, and improved synthetic tractability.
MORF-627 – In addition to GSK, Morphic disclosed the discovery story for their oral αvβ6 integrin inhibitor, MORF-627. X-ray structures of hit compounds bound to αvβ6 and related integrins guided optimization to enhance potency and selectivity, leveraging FEP+ calculations for accelerated structure-based design. Further refinement of PK properties, including permeability, bioavailability, clearance, and half-life, led to the discovery of MORF-627, which has good oral PK and stabilizes the bent-closed conformation of αvβ6. Although MORF-627 exhibited toxicity in a 28-day NHP (non-human primate) safety study, halting clinical development and any potential licensing deals with AbbVie and J&J, it may serve as a valuable tool compound for interrogating integrin αvβ6 biology.
BAY2413555 – A PAM (positive allosteric modulator) of the M2R (M2 muscarinic acetylcholine receptor) from Bayer designed to restore autonomic balance in heart failure patients. M2R, the primary postsynaptic receptor in cardiac myocytes, regulates heart rate, electrical conduction, and contractile strength, making it a key target for addressing vagal withdrawal—a critical driver of autonomic disbalance in heart failure. The discovery of BAY 2413555 originated from an HTS campaign followed by extensive optimization of potency, permeability, metabolic stability, and solubility. While the discovery journey of BAY 2413555 was recently presented by Alexandros Vakalopoulos of Bayer at the EFMC-ISMC 2024 joint conference in Rome and progressed to a Ph. I trial (NCT05532046) in patients with heart failure, it was terminated “due to new preclinical findings in a chronic toxicology study.”
compound 7o – Roche’s highly potent and selective MAGL (monoacylglycerol lipase) inhibitor designed for the treatment of CNS disorders associated with neuroinflammation. MAGL plays a critical role in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid implicated in CNS pathophysiology. The discovery of compound 7o, which adds another asset to Roche’s MAGL portfolio, began with a reversible benzoxazinone hit identified through focused screening of a Roche library subset. Replacing the benzoxazinone core with a novel cis-hexahydro-pyrido-oxazinone scaffold improved MAGL potency and led to improved ADME properties. Compound 7o has CSF exposure following systemic administration in rodents, effectively engaging its CNS target and modulating neuroinflammatory pathways.
NP10679 – A pH-sensitive, GluN2B-selective NMDA receptor inhibitor from Neurop with potential as a neuroprotective agent for aSAH (aneurysmal subarachnoid hemorrhage). Cerebral vasospasm and delayed cerebral ischemia following aSAH are linked to elevated extracellular glutamate levels, which over-activate NMDA receptors and cause cellular damage. NP10679 is designed to exhibit increased potency under the acidic extracellular pH conditions associated with ischemia, making it a targeted approach to mitigating secondary ischemic injury. In a murine model of aSAH, NP10679 shows superior efficacy in improving long-term neurological outcomes compared to nimodipine, the current standard of care. Importantly, PK studies revealed no DDIs between NP10679 and nimodipine, supporting its use as a complementary therapy. NP10679 has been advanced to Ph. I trials in healthy volunteers.
MMV371 (mCBE161) – A clinical candidate from Medicines for Malaria Venture and Quotient Sciences for malaria prophylaxis, developed as a long-acting injectable acetic acid ester prodrug of atovaquone, designed for intramuscular administration. In comparative studies with other prodrug candidates, MMV371 demonstrates sustained atovaquone plasma concentrations above the minimal efficacious level for over 30 days in cynomolgus monkeys after a single 20 mg/kg dose. Its PK profile reflects optimized very low aqueous solubility and depot release kinetics. MMV371 has advanced to a Ph. I trial (NCT06558643) in healthy volunteers and, if successful, could be a game-changer in malaria prevention.
compound 10 – AstraZeneca published their work on the de novo identification of molecular glues that stabilize the PPI (protein-protein interaction) between the GR (glucocorticoid receptor) and 14-3-3 proteins. GR is regulated not only by ligand-driven activation but also by post-translational modifications like phosphorylation, which enable GR's interaction with 14-3-3, adding complexity to its regulatory network. Using an HTS strategy, 8,000 compounds were evaluated, yielding a singleton hit that was the basis for a limited SAR effort using biophysical assays, 1D and 2D NMR spectroscopy, and SAR studies. Among the 10 compounds tested, triazolone 10, characterized by a benzyl S-substituent, emerged as the most effective stabilizer of the GR–14-3-3 interaction. Compound 10 not only helps to validate the concept of GR–14-3-3 molecular glues but also serves as a promising tool compound to further investigate the physiological significance of this PPI.
sepiapterin – An orally bioavailable tetrahydrobiopterin precursor from Censa Pharma and PTC Therapeutics being developed for the treatment of PKU (phenylketonuria), a condition characterized by neurotoxic Phe (phenylalanine) accumulation, now has published Ph. III (NCT05099640) data. During the initial 14-day open-label phase, 73% of participants demonstrated a response to sepiapterin and in a subsequent six-week randomized, double-blind phase, sepiapterin treatment achieved a significant 63% reduction in blood Phe levels compared to placebo. The therapy was well-tolerated, with treatment-emergent adverse events, primarily mild GI issues, reported in 59% of sepiapterin-treated participants versus 33% in the placebo group. In July, PTC Therapeutics refiled their NDA for sepiapterin with the FDA after a series of regulatory setbacks last year. Other companies are also exploring treatments for PKU, such as Jnana Therapeutics with its oral allosteric SLC6A19 inhibitor, JNT-517. The company made headlines in August when Otsuka Pharmaceutical announced its acquisition of Jnana Therapeutics in a deal potentially worth over $1.1B.
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