We’re here at ACS Chicago 2022, covering sections of particular interest to drug discovery scientists. Among the highlights are the First Disclosures sections, where companies are sharing structures of clinical candidates for the first time. We’ll go more in-depth into the science from the conference soon – for now, here’s a high-level summary:
Structure of the Nimbus TYK2 Inhibitor
One of the highlights today is NDI-034858, Nimbus’s TYK2 inhibitor in Ph. II trials for psoriasis:
The molecule remarkably covers human IC90 for 24 h at low doses of 35-50 mg orally.
Long viewed as the most likely drug to be approved for TYK2 after BMS’s deucravitinib (FDA decision expected any day now), Nimbus’s TYK2 molecule development was stalled by BMS’s acquisition of Celgene, which had partnered with Nimbus to develop the molecule. This led to a legal battle between Nimbus and BMS, which ultimately was resolved by Nimbus reacquiring rights to its TYK2 inhibitor.
Computational chemistry (FEP) was employed extensively during discovery, in partnership with Schrodinger. The success of this program may have helped catalyze Schrodinger’s launch of its own internal drug discovery pipeline.
The molecule is structurally distinct from deucravacitinib, and is a Type IV allosteric inhibitor by binding to the pseudokinase JH2 domain, though its binding mode to the JH2 domain is reminiscent of Type I binders, with the pyrazolopyrimidine acting as the hinge binder.
TYK2 inhibitor development will continue to be hotly followed after deucravitinib, with eyes on this molecule and the Alumis (Esker) molecule in particular as followers.
Additional First Disclosures from ACS 2022
The other molecules included:
GS-4224, an oral PD-L1 dimerizer and inhibitor from Gilead Sciences – it completed a Ph. I in HV and was intended for cancer, though uses in virology may be explored (HBV, HIV). Interestingly, potency increased with PD-L1 expression due to the dimerization mechanism
Compound 17, an MRGPRX2 antagonist from GlaxoSmithKline – an interesting N-oxide for the treatment of mast cell diseases
AZD4831, a myeloperoxidase (MPO) inhibitor from AstraZeneca – a Ph. IIa for heart failure w/ preserved ejection fraction with a 2.5-5 mg QD dose. Secondary endpoints were met, including an increase in 6 min walk distance.
PF-07258669, a melanocortin-4 receptor (MC4) antagonist from Pfizer – in contrast to MC4 agonists intended for weight loss, it is a Ph. I candidate to increase weight gain, though specific indications were undisclosed.
Onfasprodil, an NR2B-selective NAM from Novartis – it’s a Ph. IIb candidate and rapid-acting antidepressant. Interestingly, during development, the team applied the first in vivo PET receptor occupancy studies w/ an NMDA ligand, a longstanding goal in the NMDA field. It has once-weekly IV dosing with rapid onset of action
MK-3402, a pan-beta-lactamase inhibitor from Merck – it has activity against serine- and zinc-beta-lactamases with a projected dose of 75 mg IV once every 6 hours. Sadly the clinical program discontinued for strategic reasons
GLPG3970, a SIK2/3 inhibitor from Galapagos – it’s a Ph. IIa candidate for inflammatory diseases, optimized from a pan-SIK inhibitor. Sadly it was discontinued due to limited clinical efficacy
FLX475, a CCR4 antagonist for immuno-oncology from RAPT Therapeutics – a Ph. II I/O candidate w/ efficacy in cancers, it has oral, once-daily dosing, and reduces regulatory T-cell trafficking to tumors with efficacy in some patients as a single agent
AB-836, an HBV capsid inhibitor from Arbutus – it’s a Ph. Ia/Ib candidate for HBV with a novel binding mode at the dimer-dimer interface. Unfortunately, due to ALT elevations in Ph. I patients, it’s returned to a healthy volunteer study for derisking.
Hope this is helpful! We’ll have deeper dives on each molecule and more highlights from ACS on drughunter.com soon. Stay tuned!