Molecules of the Month

May 2024

In May, AstraZeneca reported positive Ph. I results for their oral small molecule PCSK9 inhibitor. PMV Pharma’s potential first-in-class p53 Y220C reactivator and Janssen’s selective OX2R (orexin-2 receptor) antagonist with positive Ph. III results are also featured this month. Additional molecules we found notable from May include a saxitoxin-derived NaV1.7 inhibitor from SiteOne Therapeutics and Biogen’s brain-penetrant BTK (Bruton’s tyrosine kinase) inhibitor.

You can find out what compounds made our May 2024 Molecules of the Month list and check out recent articles for each linked below:

  1. AZD0780 – An oral small molecule PCSK9 inhibitor discovered by Dogma Therapeutics and being developed by AstraZeneca for patients with dyslipidaemia that cannot be controlled with statins alone. Positive Ph. I trial (NCT05787002) results were presented at the European Atherosclerosis Society Congress 2024 in Lyon, France showing a statistically significant reduction of 52% in LDL-C levels on top of rosuvastatin treatment, with 78% total reduction from baseline, in treatment-naive participants with hypercholesterolaemia with no serious adverse events reported. AZD0780 progressed to a Ph. II (NCT06173570) trial in patients with dyslipidaemia earlier this year. While AstraZeneca is playing catch-up to Merck’s MK-0616, Drug Hunter’s 2023 Molecule of the Year, the industry is closely watching how these oral PCSK9 inhibitors differentiate in the clinic. 

  2. rezatapopt – PMV Pharma’s first-in-class oral small molecule designed to reactivate p53 by selectively binding to the p53 Y220C mutant protein, thereby restoring wild-type p53 tumor suppressor function. The FDA has granted Fast Track designation to rezatapopt for treating patients with locally advanced or metastatic solid tumors harboring the p53 Y220C mutation. Rezatapopt is currently being evaluated in a Ph. II trial (NCT04585750) alone and combination with pembrolizumab in participants with advanced solid tumors containing a TP53 Y220C mutation.

  3. sonrotoclax (BGB-11417) – A potent, selective, and orally bioavailable wild-type and Bcl-2 G101V mutant inhibitor with remarkable selectivity over Bcl-xL from BeiGene. Comprehensive structure optimization studies, starting from the first U.S.-approved Bcl-2 inhibitor, venetoclax, led to the clinical candidate, which features a phenylpyrrolidine fragment for shallow and broad P2 pocket interaction and a rigid 7-azaspiro[3.5]nonane linker for enhanced binding. Currently undergoing Ph. II/III clinical assessments as a monotherapy and combination treatment, BGB-11417 has demonstrated superior in vitro activity and in vivo efficacy compared to venetoclax. 

  4. BMS-986308 – A potent and orally bioavailable ROMK (renal outer medullary potassium) inhibitor discovered and currently in development by Bristol Myers Squibb as a diuretic in heart failure patients. BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model, exhibited a promising preclinical profile, and has advanced to a Ph. I trial (NCT04763226) in healthy participants. 

  5. seltorexant – Janssen’s potential oral first-in-class selective OX2R (orexin-2 receptor) antagonist that met all primary and secondary endpoints in a pivotal Ph. III (NCT04532749) study in patients with major depressive disorder (MDD) with insomnia symptoms. If approved, seltorexant will be the first medication specifically targeting MDD patients who also suffer from insomnia. 

  6. KSQ-4279 (RO7623066) – An oral selective USP1 (ubiquitin-specific protease) inhibitor that binds to the same cryptic site as the well-known tool compound ML323 but disrupts the protein structure in subtly different ways. In 2023, KSQ Therapeutics entered a worldwide license and collaboration agreement with Roche to progress KSQ-4279 into a Ph. I trial (NCT05932862) in patients with advanced solid tumors. Notably, in May, Tango announced the discontinuation of their structurally related clinical USP1 inhibitor, TNG348, due to the observations of grade 3/4 liver function abnormalities in patients dosed for longer than eight weeks.

  7. cadazolid – An oral first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of Clostridioides difficile protein synthesis from Idorsia that progressed to Ph. III trials (NCT03105479) in 2017, but has since been terminated.

  8. BIIB129 – An oral brain-penetrant targeted covalent inhibitor of BTK discovered by Biogen with a unique binding mode responsible for high kinome selectivity. Preclinically, BIIB129 demonstrated efficacy in disease-relevant in vivo models of B cell proliferation in the CNS and exhibits a clean safety profile suitable for clinical development as an immunomodulating therapy for MS (multiple sclerosis). 

  9. ST-2560 – SiteOne Therapeutics’ potent, selective, and state-independent NaV1.7 inhibitor derived from the natural NaV1.7 inhibitor, saxitoxin, as a potential non-opioid analgesic. While antinociceptive, ST-2560 also appears to impact the cardiovascular system based on measured haemodynamic parameters. At the ACS Spring 2024 Meeting, SiteOne’s co-founder, John Mulcahy, disclosed the discovery and optimization of ST-2560 (“compound 6”). Check out our full series on the history, target validation, and competitive landscape of voltage-gated sodium channels to learn more. 

  10. ifebemtinib – A highly selective, orally bioavailable FAX (focal adhesion kinase) inhibitor discovered by Boehringer Ingelheim and being developed by InxMed, that synergies with a broad spectrum of therapeutic modalities in the clinic. An interim analysis of the ongoing Ph. Ib/II trial (NCT06166836) presented at the 2024 Annual ASCO Meeting in Chicago, showed that ifebemtinib in combination with the KRAS G12C inhibitor, garsorasib, in subjects with locally advanced or metastatic solid tumor with KRAS G12C mutation leads to an overall response rate of 90.3% and a disease control rate of 96.8%. 

Reviewer Commentary on Biogen’s BIIB129 from Charles Cole

In the continued pursuit of BTK inhibition as a potential therapeutic option for oncology and autoimmune indications, the field has produced several targeted covalent inhibitors (e.g., ibrutinib, accalabrutinib, tolebrutinib), non-covalent inhibitors (e.g., pirtobrutinib, fenebrutinib, BMS-986142) and even a degrader (e.g., NX-2127). Despite this congested competitive landscape, Biogen asserts that there is still room for another contender. They highlight that most other approved drugs or clinical candidates demonstrate profiles that are sub-optimal for CNS drugs. As such, their campaign focused on generating a molecule with improved CNS penetrance, in hopes of increasing efficacy while reducing the dose body burden. In the hit-to-lead stage, the authors decided to take a minimalist design approach, only proposing and pursuing compounds with a hinge binding region, a covalent warhead and an sp3-rich linker between the two. While growing into the gatekeeper or H3 regions could provide improvements in potency, there was concern that the necessary increase in molecular weight and/or lipophilicity would negatively affect brain penetrance. Instead, following the identification of the pyrazolopyrazine core, the authors place attention on the optimization of the sp3-linker both to drive potency and improve ADME. In the end, this linker proves key to their success. Not only are they able to improve clearance by altering ring size and substitution, but many of the promising linkers introduce an additional H-bond between the carbonyl of the warhead and Asn484. The authors speculate that this polar interaction is responsible for the strong kinase selectivity compared to other notable BTK inhibitors. Through these efforts, they identified BIIB192, which showed improved potency, cross-species PK, and brain exposure in rodents. With proven IVIVC data demonstrating inhibition of B-cell and microglia activity in the CNS, good kinome selectivity, and great preclinical toxicology, Biogen may just have found a way to differentiate themselves from the multitude of candidates both on the market and in the clinic.


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