November’s Molecules of the Month features GSK’s small-molecule IBAT inhibitor designed to alleviate relentless itch, and Novartis’ TAK1 inhibitor for osteoarthritis, showcasing a fascinating drug design and delivery strategy to maximize joint concentration while minimizing systemic exposure. Additionally, we highlight a clinical-stage, long-acting inhaled ENaC inhibitor for cystic fibrosis, a highly soluble prodrug of a potent capsid assembly modulator for HBV, and innovative macrocyclic CDK7 and NLRP3 inhibitors.
You can read more about the compounds that made our November 2024 Molecules of the Month list and check out recent articles for each, linked below:
linerixibat – GSK’s IBAT (ileal bile acid transporter) inhibitor, is an oral therapy developed to treat cholestatic pruritus associated with PBC (primary biliary cholangitis). By blocking bile acid reuptake in the small intestine, linerixibat reduces circulating bile acids that drive relentless itching in PBC patients. Granted Orphan Drug designation by the FDA and EMA, linerixibat achieved its primary endpoint in a Ph. III trial (NCT04950127), demonstrating a statistically significant reduction in itch scores after 24 weeks compared to placebo. Preliminary safety results were consistent with earlier studies, positioning linerixibat as a potential first-in-class global therapy for itch in PBC. While GSK plans regulatory discussions, competitors Ipsen and Mirum Pharmaceuticals are advancing their IBAT inhibitors (BylvayTM and volixibat, respectively) for related indications.
TAK-756 – A potent and selective TAK1 (transforming growth factor β-activated kinase 1) inhibitor from Novartis developed for intra-articular injection to treat OA (osteoarthritis), a chronic joint disease with no disease-modifying treatments. Designed for high drug exposure at the joint while minimizing systemic exposure and associated toxicities, TAK-756 was optimized through structure-based design to improve kinase selectivity (notably against IRAK1/4) and intra-articular PK. Interestingly, Novartis’ drug design hypothesis involved increasing the crystallinity, reducing solubility in synovial fluid, and maintaining low lipophilicity to optimize free drug concentration at the target site. TAK-756 demonstrates robust anti-catabolic and anti-inflammatory activity in vitro, prolonged joint exposure in rats, and dose-dependent reductions in inflammatory markers (Cxcl1, Mmp3, and Il6) in a rat joint inflammation model. Though the company says no further development is planned, TAK-756 represents an interesting tool for exploring TAK1 biology in inflammatory joint diseases.
ETD001 – Enterprise Therapeutics’ ENaC (epithelial sodium channel) inhibitor, with Rare Pediatric Disease designation from the FDA, potentially offers a complementary approach to CFTR modulators for improving airway hydration in CF (cystic fibrosis). Developed through stepwise optimization of a pyrrolopyrazine scaffold, ETD001 incorporates a quaternary benzimidazole group and polyhydroxylated tails to enhance polarity, reducing passive permeability and promoting retention in airway surface fluid. ETD001 demonstrates potent ENaC inhibition, prolonged airway retention in rats (13% of the dose after 6 h), and a long-lasting effect in a sheep mucociliary clearance model (ED100 = 9 μg/kg for 4–6 hours). Well-tolerated in a Ph. I trial (NCT04926701), ETD001 advanced to Ph. II trials (NCT06478706) in July 2024 in patients with CF with a study completion date scheduled in the summer of 2025. Notably, several other ENaC-blocking drugs (VX-371, AZD5634, BI 1265162, QBW276) failed to show any benefit in clinical trials, so the industry will be closely watching for any signs of clinical efficacy and differentiation here.
prodrug ALG-000184 – Aligos Therapeutics’ ALG-000184 is a highly soluble phosphate prodrug of the potent HBV (hepatitis B virus) CAM (capsid assembly modulator) ALG-001075, originating from the known CAM, GLP-26, for the treatment of CHB (chronic hepatitis B). In clinical trials (NCT04536337), oral dosing of ALG-000184 led to remarkable reductions in HBV DNA, RNA, and viral antigens in HBV-infected subjects. These results position ALG-000184 as a promising candidate for chronic suppression and combination regimens, potentially improving functional cure rates for CHB.
compound 39 – A macrocyclic next-generation NLRP3 (nucleotide-binding domain, leucine-rich repeat family pyrin domain containing 3) inflammasome inhibitor from Roche designed to address limitations of first-generation sulfonylurea inhibitors, like Pfizer’s MCC950 (CP-456,773; CRID3), including moderate potency and DILI (drug-induced liver injury). Through conformational studies and NOE-guided design, this macrocyclic inhibitor, incorporating an acyl sulfonamide chemotype, did help to improve ADME properties and reduce DILI risk. Despite potent in vitro activity and a scalable synthesis, high in vivo clearance limited efficacy in an LPS model due to insufficient IL-1β suppression. To explore the competitive landscape of NLRP3 inhibitors, check out our past coverage.
compound 23 – The KEAP1/Nrf2 axis remains a focus for many companies following the FDA approval of the KEAP1 blocker/Nrf2 activator omaveloxolone, with Vividion Therapeutics notably disclosing both Nrf2 inhibitors and activators this year. Now Servier is joining this crowded space with their own covalent inhibitor of KEAP1 (represented by the thiazole-containing compound 23). Identified through phenotypic screening and optimized via systematic SAR, this covalent thiazole chemotype demonstrates robust cellular and in vivo activity, with no genotoxicity or significant off-target interactions across >6,000 proteins in activity-based protein profiling. X-ray crystallography revealed the molecular mechanism of KEAP1 inhibition, revealing the interactions driving the selectivity of compound 23. This could be a potential new platform for designing selective covalent inhibitors for other targets.
ATX968 – Accent Therapeutics‘ potent and selective DHX9 inhibitor, a multifunctional DExH-box RNA helicase essential for transcription, translation, and genome stability. Elevated DHX9 expression is critical in MSI-H (microsatellite instability-high) tumors with dMMR (deficient mismatch repair). Inhibiting DHX9 with ATX968 induces RNA/DNA secondary structures, replication stress, cell cycle arrest, and apoptosis, selectively impairing MSI-H/dMMR cancer cells. Preclinically, ATX968 demonstrates robust efficacy in MSI-H/dMMR xenograft models while sparing MSS (microsatellite stable)/pMMR (proficient mismatch repair) models. Accent Therapeutics appears to be the first to publicly disclose a program targeting DHX9, with poster presentations at the AACR-NCI-EORTC Symposium 2023 and the GRC DNA Damage, Mutation, and Cancer 2024 meeting, positioning the company as a potential leader in DHX9 space. Check out our September 2024 Patent Highlights to learn more about their DHX9-targeting chemical matter and our case studies on HRO761 and VVD-214 to learn more about the WRN helicase and MSI-high cancers.
GS-2278 – GS-2278 is Gilead’s potent, non-brain-penetrant (desirable given its role in neurodevelopment), and orally bioavailable LPAR1 (lysophosphatidic acid receptor 1) antagonist with a direct-acting antifibrotic mechanism. Developed through structural optimization of non-carboxylic acid LPAR1 antagonists (for example, Idorsia’s ACT-1016-0707), GS-2278 overcame challenges such as metabolic instability and GSH adduct formation observed with earlier leads. It demonstrates a favorable in vitro profile, suitable PK for oral QD dosing, and efficacy in blocking LPA-induced histamine release and mitigating bleomycin-induced lung fibrosis in preclinical models. However, CNS-related toxicity in dogs led to the discontinuation of its clinical development for IPF (idiopathic pulmonary fibrosis).
compound 13 – Developed through the core component of Insilico Medicine’s Pharma.ai drug discovery suite, Chemistry42, and extensive SAR/ADME optimization from Syros’ covalent CDK7 inhibitor SY-5609, compound 13 appears to address the challenges of gastrointestinal and hematotoxic side effects in preclinical studies associated with previous CDK7 inhibitors. This phosphine oxide-containing (check out Gilles Ouvry’s recent discussion on the permeability of phosphine oxides here), macrocyclic, noncovalent inhibitor demonstrates potent in vitro CDK7 activity, favorable ADME properties, robust anti-tumor efficacy in xenograft models, and is well tolerated up to 100 mg/kg in a single-dose escalation PK study in rats with high levels of oral exposure. Its reduced basicity enhances Caco-2 permeability, lowers the blood/plasma ratio, and minimizes intestinal distribution in rats, which may translate to a more tolerable toxicity profile in the clinic.
alisertib – The AURKA (Aurora kinase A) inhibitor alisertib, originally discovered by Millenium Pharmaceuticals (acquired by Takeda in 2008), has been evaluated in 64 clinical trials to date. It was recently studied in combination with pembrolizumab (Keytruda) for patients with advanced solid tumors and immunotherapy- and platinum-resistant HPV (human papilloma virus)-positive HNSCC (head and neck squamous cell carcinoma). In this Ph. II trial (NCT04555837), alisertib dosed orally at 40 mg twice daily (days 1–7 of a 21-day cycle) demonstrated tolerable toxicity, with expected cytopenia as the primary adverse effect. While no objective responses were observed, prolonged SD (stable disease) occurred in heavily pretreated patients, including ≥6 months of SD in 4 out of 15 HPV-positive participants. The combination was pharmacokinetically compatible and correlated with higher levels of HLA-DR–expressing NK cells in SD patients, suggesting a role in reversing immunotherapy resistance in retinoblastoma protein-deficient HNSCC. In September 2022, Puma licensed global rights to alisertib from Takeda. Since then, Puma has initiated several clinical trials to evaluate alisertib’s efficacy in various cancer types, including SCLC (small cell lung cancer), for which it has received Orphan Drug designation, and metastatic breast cancer (Ph. II, NCT06369285).
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