We asked the global drug discovery community to nominate and vote on their favorite molecule from 2022, and the results are in. The 2022 winner, with the most overall votes across the ten finalist molecules, is BMS’ oral, deuterated allosteric TYK2 inhibitor, deucravacitinib, the first new treatment for plaque psoriasis in nearly a decade. Here, we highlight what makes deucravacitinib so impressive to the drug discovery community.
The First Pseudokinase-Targeting TYK2 Inhibitor and First Novel Deuterated Drug
Deucravacitinib selectively modulates the activity of JAK family member, TYK2, through binding to the non-catalytic JH2 pseudokinase domain. This contributes to its significant anti-inflammatory efficacy while avoiding many undesirable effects attributable to JAK1/2 inhibition. The molecule was the first allosteric TYK2 inhibitor to enter clinical trials, is the first JAK-family kinase inhibitor approved for psoriasis, and is also the first approved drug targeting a pseudokinase domain.
The superior selectivity for the non-catalytic JH2 pseudokinase domain vs. JH1 catalytic kinase domains on JAK enzymes is attributed to a “magic methyl” on the amide moiety, which is protected from metabolic cleavage via deuteration. The molecule is the first approved deuterated drug in which the deuterated version was the first to be approved (in contrast to deutetrabenazine, which came after tetrabenazine). The development of a commercial manufacturing process involving deuterated building blocks is notable given the fact that the non-deuterated species has different pharmacology (lower selectivity due to an active metabolite), presenting a significant CMC challenge that needed to be overcome.
The molecule is believed to become a new standard of care in more than one indication, and is considered to be a potential megablockbuster for manufacturer and originator Bristol Myers Squibb. With a remarkable pseudokinase-targeting mode of action discovered only through an unconventional phenotypic screening approach for kinase inhibitors, and its deuterated structure, the molecule brings a combination of scientific novelty and clinical impact that left an impression on readers.
The Vote and Runners-Up
#1: Deucravacitinib (Bristol Myers Squibb, 24%)
Deucravacitinib stands out even with an impressive cohort of competitive nominees for 2022, with the runners-up shown below.
#2: MRTX1133 (Mirati Therapeutics/Array BioPharma, 21%)
The 2nd place runner-up is MRTX1133, the non-covalent KRAS(G12D) inhibitor and is the first reported inhibitor specific for G12D, which makes up as much as 33% of all KRAS mutations and carries a 2 to 3-fold higher disease burden than G12C. A recent preclinical study demonstrated that MRTX113 was able to reduce tumor size in KPC mice, a pancreatic cancer model that is resistant to every drug tested. MRTX1133 is currently in Ph I/II trials as an oral agent.
#3: YCT529 (University of Minnesota, Georg lab, licensed by YourChoice Therapeutics, 13%)
In third place was YCT529, from UMN/YourChoice Therapeutics. The Georg lab at the University of Minnesota worked on male contraceptives for over 10 years, and was inspired by BMS’ pan-RARalpha antagonists that exhibited testicular toxicity. As a non-hormonal oral drug, YCT529 targets RARalpha, which is involved in both Vitamin A metabolism and sperm production, and appears to work tolerably and reversibly in preclinical studies. The excitement is high as if successful, this could be the first non-hormonal oral male contraceptive to be broadly useful.
#4: LP0200 (Leo Pharma, 9%)
In 4th place is Leo Pharma’s LP0200, an oral IL-17A protein-protein interaction modulator prodrug for psoriasis. Through a series of structure-based design, ADME and solubility optimization, LP0200 was shown to exhibit high potency and safety comparable to approved IL-17A and IL-17RA targeting mAbs (more in our report of first disclosures from the EFMC-ISMC and this article on small molecule immunomodulators). LP0200 has completed a Ph. I trial.
#5: Emraclidine (Cerevel Therapeutics/Pfizer, 6%)
In 5th place is emraclidine, Cerevel/Pfizer’s selective, brain-penetrant positive allosteric modulator of the M4 receptor, for the treatment of schizophrenia and Alzheimer’s disease psychosis. Targeting the M4 receptor has been an attractive alternative to dopamine receptors, as these drugs are associated with side effects such as cardiovascular issues. Emraclidine was developed by rational design and is the only selective M4 PAM in clinical trials. For more coverage, visit December 2022’s MOTM.
Why Deucravacitinib is Interesting to Drug Hunters
We asked what was impressive or important about the molecule to drug discovery scientists and here’s some of what was said:
- “Impressive efficacy and cool MOA (novel allosteric pocket to achieve selectivity within JAK family)” Gabe Simon, VP, Head of Early Discovery and Enabling Technologies of Vividion Therapeutics
- “Great med chem story for a first-in-class molecule” Rob Mazzola, Director at Merck
- “First allosteric kinase inhibitor, first TYK2 inhibitor, using a phenotypic screen to discover starting point, incorporated deuterated atoms for clearance optimisation” Steven Van der Plas, Director of Medicinal Chemistry at iTeos Therapeutics
- “New mechanism (pseudokinase!) and use of deuterium” Jonathan Rosenblum, VP Research at ActivX Biosciences
- “An impressive compound that targets the JH2 domain in order to gain functional selectivity and is now a launched drug. The use of deuterium to redirect metabolism is very clever.” Mark Andrews, Senior Principal Scientist at LEO Pharma
- “First pseudokinase inhibitor and first de novo deuterated molecule approved: demonstrates great problem-solving teamwork and, furthermore, illustrates that there is still space for innovation in the kinase inhibitor field” Michele Modugno, Scientific Project Leader at Eurofins
- “BMS has made groundbreaking contributions in the field of TYK2 JH2 inhibition by developing two independent chemical structure series, one of which is deucravacitinib and another which showed good competitiveness.” Changqing Wei, Associate Director, Medicinal Chemistry, WuXi
We’ll be covering more on the science behind the discovery, development, and impact of deucravacitinib soon – sign up for our newsletter so you don’t miss the next part when it releases!
