Molecules of the Month

March 2024

In March, Crinetics Pharmaceuticals revealed their discovery of CRN04894, a first-in-class nonpeptide melanocortin type 2 receptor (MC2R) antagonist which is currently being evaluated in several Ph. II trials. Additional molecules to make the top ten include a preclinical, brain-penetrant casein kinase 1 delta (CK1δ) inhibitor and a WT-sparing phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) H1047R inhibitor. Galapagos SASU and AbbVie disclosed the discovery story of their orally bioavailable cystic fibrosis transmembrane conductance regulator (CFTR) protein C2 corrector that has subsequently been terminated in a Ph. II trial for kidney disease. Also featured this month is a CNS-penetrant interleukin 1 receptor-associated kinase 4 (IRAK4) inhibitor from Biogen and an emopamil-binding protein (EBP) inhibitor from Genentech and Convelo Therapeutics.

You can check out the recent articles about the March 2024 Molecules of the Month linked below:

  1. CRN04894 – A potent and subtype-selective first-in-class nonpeptide MC2R antagonist from Crinetics Pharmaceuticals, which demonstrated efficacy in a rat model of adrenocorticotropic hormone (ACTH)-stimulated corticosterone secretion. CRN04894 is currently being evaluated in a first-in-disease Ph. Ib/IIa trial (NCT05804669) in participants with ACTH-dependent Cushing's syndrome and a Ph. II trial (NCT05907291) in participants with congenital adrenal hyperplasia. 

  2. compound 17 – A potent, WT-sparing PI3Kα H1047R inhibitor from Mirati that led to tumor regressions in an HCC1954 tumor mouse mode. X-ray cocrystal structures of several related analogs bound to PI3Kα H1047R revealed three unique binding modes. Based on the increasingly competitive activity around this pyridopyrimidinone scaffold, including patent disclosures from Relay, Fochon, and Zeno Management, Mirati deprioritized this series for further development. Drug Hunter has previously profiled other PI3Kα inhibitors, including inavolisib, STX-478, and RLY-2608.

  3. compound 21 – A preclinical, brain-penetrant CK1δ inhibitor from Janssen that has a unique hinge-flip binding mode, is highly selective versus the kinome, and is intended for the treatment of sleep disorders.  

  4. GLPG2737 – An orally bioavailable, potent, and structurally unique CFTR protein C2 corrector from Galapagos SASU and AbbVie with demonstrated efficacy in rescuing CFTR function. Notably, GLPG2737 is mechanistically distinct from elexacaftor and exerts functional synergy with a potentiator and C1 co-corrector. In 2020, GLPG2737 advanced to a Ph. IIa trial (NCT04578548) to evaluate its efficacy in subjects with autosomal dominant polycystic kidney disease but was ultimately terminated. 

  5. AZD5462 – A potent and selective pharmacological mimetic of relaxin H2 signaling at relaxin family peptide receptor 1 (RXFP1) from AstraZeneca and Mitsubishi Tanabe that was assessed in a translatable cynomolgus monkey heart failure model and showed improvements in functional cardiac parameters. AZD5462 has advanced to a Ph IIb trial (NCT06299826) to evaluate its effect on cardiac function in participants with chronic heart failure. 

  6. HC-7366 – An oral, selective activator of the serine/threonine-protein kinase general control nonderepressible 2 (GCN2) from HiberCell and Pharmaron exhibiting improved ADME properties compared to earlier generation inhibitors possessing an indazole-based hinge binder. HC-7366 is being evaluated in a Ph. Ib trial (NCT06234605) as a monotherapy and in combination with belzutifan in patients with locally advanced metastatic renal cell carcinoma. 

  7. GLPG3970 – A first-in-class dual salt-inducible kinases 2 and 3 (SIK2/SIK3) inhibitor with selectivity against SIK1 from Galapagos SASU, which represents a new therapeutic approach for the treatment of inflammatory diseases. GLPG3970 has advanced to Ph. II trials to evaluate its efficacy in patients with moderate to severe ulcerative colitis (NCT04577794) and rheumatoid arthritis (NCT04577781), and a Ph. I trial for lupus (NCT04700267). 

  8. BIO-7488 – A potent, selective, and CNS-penetrant IRAK4 inhibitor with excellent ADME properties from Biogen for the treatment of neuroinflammation. BIO-7488 was evaluated in CNS PK/PD models of inflammation and a mouse model of ischemic stroke.

  9. compound 11 – A brain-penetrant, orally bioavailable hydantoin-based inhibitor of EBP from Genentech and Convelo Therapeutics. EBP is a sterol isomerase in the cholesterol biosynthesis pathway that promotes oligodendrocyte formation and is proposed to be a potential therapeutic target for treating multiple sclerosis. Compound 11 exhibited strong in vivo target engagement in the brain in mice, and enhanced the formation of oligodendrocytes in human cortical organoids.

  10. NMD670 – An orally bioavailable skeletal muscle-specific chloride ion channel (ClC-1) inhibitor from NMD Pharma that was shown to restore muscle function in rat models of myasthenia gravis (MG). NMD670 is currently being evaluated in a Ph. II trial (NCT05794139) in adults with type 3 spinal muscular atrophy.

Reviewer Commentary on Mirati’s Compound 17 from Charles Cole

The PI3K family is quite familiar to the drug-hunting community, with many programs centered around the various isoforms of the p110 catalytic subunit (namely PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ). Of these isoforms, PI3Kα has been shown to play a key role in the progression of various solid tumors, typically through gene overexpression because of gene amplification and/or activating mutations. While there exists a single clinically approved inhibitor of PI3Kα (alpelisib) there are challenges related to inhibition of the WT protein given its essential role in standard cellular functions and often resulting in toxicity concerns (mainly hyperglycemia). Many subsequent molecules have taken this into account and instead focus on so-called “pan-mutant” inhibition, wherein there is selective inhibition or degradation of various mutants over WT. I would note that Drug Hunter has also profiled many of these molecules previously (inavolisib, STX-478, and RLY-2608).” 

“The approach taken by the Mirati team places a lot of focus on the use of structure-based drug design, allowing modeling and X-ray crystal structures to guide much of the presented SAR. Starting from a series of literature-reported compounds, the team found a molecule that not only bound to the orthosteric site but also a separate allosteric site, proximal to the mutation of interest (H1047R). This use of an allosteric binding pocket to obtain selectivity for mutant over WT is reminiscent of the strategy now common for the targeting of KRAS mutants. From there, a routine SAR campaign brought them to compound 17, a molecule that exhibits good potency and selectivity for the H1047R mutant as well as promising PD and efficacy data. While the authors indicate that the series was discontinued due to the competitive landscape around this scaffold, it is still a well-reasoned approach and classic application of structure-based drug design.

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