First Disclosures from ACS Chicago 2022

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:

Chemical structures of 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) agonist from @Pfizer – in contrast to MC4 antagonists intended for weight loss, it is a Ph. I candidate to increase weight gain, though specific indications were undisclosed
NDI-034858, a TYK2 JH2-domain inhibitor from @Nimbus – a hotly followed molecule taken back from BMS in Ph. II for psoriasis and psoriatic arthritis. It has once daily oral dosing in humans and 35 and 50 mg doses cover IC90 for 24h

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/ a 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 dimer-dimer interface. Unfortunately due to ALT elevations in Ph. I patients, it’s returned to a healthy volunteer study for derisking.

Structure of the Nimbus TYK2 Inhibitor

One of the highlights today is NDI-034858, Nimbus’s TYK2 inhibitor in Ph. II trials for psoriasis:

NDI-034858 Nimbus TYK2 inhibitor chemical structure

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

GS-4224 Gilead Sciences chemical structure PD-L1 PDL1 inhibitor

Compound 17, an MRGPRX2 antagonist from GlaxoSmithKline – an interesting N-oxide for the treatment of mast cell diseases

GSK MRGPRX2 antagonist chemical structure compound 17

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.

ADZ4831 chemical structure AstraZeneca MPO inhibitor

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.

PF-07258669 MC4R agonist Pfizer chemical structure

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

onfasprodil chemical structure Novartis NR2B-selective NAM

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

MK-3402 pan-beta-lactamase inhibitor chemical structure Merck

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

GLPG3970 Galapagos SIK2/SIK3 inhibitor chemical structure

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

FLX475 chemical structure (RAPT Therapeutics) CCR4 antagonist

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.

Arbutus HBV capsid inhibitor AB-836 chemical structure

Hope this is helpful! We’ll have deeper dives on each molecule and more highlights from ACS on drughunter.com soon. Stay tuned!

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