Drug Hunter

Can the Next-Generation TYK2 Inhibitor, Zasocitinib, Raise the Bar in Plaque Psoriasis?

After strong Ph. 3 results and a completed head-to-head trial against ’s deucravacitinib (Sotyktu®), Takeda/Nimbus’ zasocitinib is emerging as a potential best-in-class oral TYK2 inhibitor.

Zasocitinib (TAK-279, NDI-034858) is an allosteric TYK2-JH2 inhibitor designed to selectively target the catalytically inactive pseudokinase domain of TYK2, avoiding the more conserved JH1 ATP-binding site shared across the JAK family.

In Takeda’s Ph. 3 Latitude PsO trials, ~70% of zasocitinib-treated patients achieved clear or almost clear skin at week 16, compared with ~10% on placebo and ~30% on the PDE4 inhibitor apremilast (Otezla®). Zasocitinib also produced substantially higher PASI90 and PASI100 responses, strengthening its case as an oral therapy with the potential to move closer to biologic-like efficacy.

Will zasocitinib pharmacologic differentiation translate into a clinically meaningful advantage over deucravacitinib?

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zasocitinib (TAK-279/NDI-034858) Zasocitinib (TAK-279) is an oral, once-daily, allosteric TYK2 inhibitor in Ph. 3 development for inflammatory diseases, including plaque psoriasis. It targets the catalytically inactive TYK2 JH2 pseud...

TPSA (topological polar surface area) is one of the most commonly used molecular descriptors in medicinal chemistry for predicting properties such as membrane permeability, transporter-mediated efflux, oral absorption, and CNS pe*******on.

In this TPSA cheat sheet, we summarize the contributions of common functional groups and heterocycles to help medicinal chemists quickly assess how structural modifications influence molecular polarity.

Read more on Drug Hunter: https://drughunters.com/4uJv7kK

Target- and ligase-first use of DCAF16 for TPD

DCAF16 is the E3 ligase harnessed for Amphista Therapeutics’s BRD9 degrader and Plexium’s SMARCA2/4 degrader. Target-first approaches have frequently uncovered DCAF16 for TPD, especially for nuclear-localized proteins. Ligand-first approaches will extend the concept further for other protein substrates.

Read more on Drug Hunter: https://drughunters.com/4evCypK

Irafamdastat: Can Dual FAAH/MAGL Inhibition Revive Endocannabinoid Drug Discovery?

BMS-986368 (irafamdastat) is an oral, potentially first-in-class dual FAAH/MAGL inhibitor that originated from Abide Therapeutics’ as ABX-1772 and is now being developed by BMS/Celgene.

The program is notable as one of the few remaining clinical efforts to target endocannabinoid metabolism after earlier FAAH inhibitors were limited by safety concerns, insufficient efficacy, or both.

By inhibiting FAAH and MAGL, BMS-986368 is designed to reduce the breakdown of anandamide and 2-AG, the two major endocannabinoids, potentially broadening endocannabinoid tone beyond FAAH inhibition alone.

Its development in MS spasticity and Alzheimer’s disease agitation will test whether this strategy can dampen neuronal hyperexcitability and neuroinflammatory stress without the broad receptor activation associated with direct cannabinoid agonists.

Read more on Drug Hunter: https://drughunters.com/4vM9ocL

During Men's Health Week, we're highlighting three programs tackling male contraception and prostate cancer with approaches that move beyond traditional paradigms.

The Drug Hunter team recently published in-depth analyses on each of these molecules:
-YCT-529: A first-in-class, non-hormonal male contraceptive that selectively targets RAR-α.
-GDC-2992: An oral, dual androgen receptor degrader and antagonist with promising early efficacy in treating patients with advanced or metastatic prostate cancer.
-Rinzimetostat (ORIC-944): A PRC2 inhibitor that might offer a unique “reprogramming” approach to AR-independent prostate tumors.

Together, these programs demonstrate how advances in receptor biology, targeted protein degradation, and epigenetic regulation are creating new opportunities across men's health.

Interested in learning more? Receive complimentary access to all three articles following a brief platform demo. Reach out or click the link below to schedule.

https://drughunters.com/4fIlXkL

In the first lecture of Module 5 on Property-Based Design, we explore the relationship between ligand potency, physicochemical properties, and drug efficacy. We highlight commonly applied design metrics including Ligand Efficiency and Lipophilic Ligand Efficiency, and discuss the importance of understanding size and lipophilicity in the context of potency. To illustrate these concepts, practical applications of these metrics in the discovery programs of PRMT5 inhibitor MRTX-1719 and the macrocyclic ALK inhibitor lorlatinib will be discussed.

We also touch on recent metrics such Ligand Reactivity Efficiency and its application to the design of covalent inhibitors.

Throughout this lecture we focus on the importance of viewing changes in ligand potency alongside changes in ligand properties and touch on the relevance of such metrics to compounds beyond typical “drug-like” space.

🎓 Happy Learning! https://drughunters.com/4elvITL

Baxdrostat (Baxfendy®) is a first-in-class oral, selective aldosterone synthase (CYP11B2) inhibitor that was FDA approved in May 2026 for hypertension and remains active in Ph. 3 clinical trials for chronic kidney disease and heart failure.

Baxdrostat demonstrates >100-fold selectivity for CYP11B2 over CYP11B1, addressing a key historical challenge in the development of aldosterone synthase inhibitors. In its development, stereochemical optimization of the tetrahydroisoquinoline core led to a 100-fold improvement in potency and 2-fold gain in selectivity, highlighting the impact of a single chiral center inversion.

It is also incredibly potent–during its development, a Ph. 2 trial was halted due to “overwhelming efficacy” based on reductions in systolic and diastolic blood pressure in hypertensive patients, supporting a low daily oral dose (1 mg and 2 mg) in Ph. 3 development.

In the registration-enabling BaxHTN Ph. 3 trial (NCT06034743), baxdrostat treatment led to clinically meaningful reductions in blood pressure at low doses of 1 and 2 mg PO QD, meeting both primary and secondary endpoints.

Baxdrostat’s positioning as a first-in-class and potential best-in-class molecule is a remarkable coup for a small company such as CinCor, given how many well-established drug discovery groups—including those of BI, Roche, Merck, and others—have been active in the space.

Read more on Drug Hunter: https://drughunters.com/4e6ps3b

Sec61 translocates proteins into the ER and can be inhibited selectively. The therapeutic hypothesis is that problematic secreted proteins causing a variety of diseases can be prevented from translocation and redirected for degradation. Sec61 inhibitors from Kezar Life Sciences were inspired from natural products, and Gate Bioscience continues to target Sec61 for selective inhibition.

Read more on Drug Hunter: https://drughunters.com/4vAnIFk

Linerixibat (Lynavoy®) is an ASBT/IBAT inhibitor FDA-approved in March 2026 for cholestatic pruritus in PBC (primary biliary cholangitis).

UDCA (ursodeoxycholic acid), the first-line treatment for PBC, can mitigate cholestasis in many patients but often fails to relieve disease-associated pruritus, a debilitating itch linked to bile acid dysregulation.

By blocking ileal bile acid reuptake, linerixibat significantly reduced pruritus in the Ph. 3 GLISTEN trial (NCT04950127), with 21% of treated patients reporting absent itch after 24 weeks.

Gastrointestinal AEs, though, were common, including diarrhea and abdominal pain. But in the context of severe, persistent itch, linerixibat highlights how tolerability must be judged against disease-specific burden and unmet need.

Read more on Drug Hunter: https://drughunters.com/4e9ETYB

With the emergence of antimalarial drug resistance to current front-line compounds, identification of first-in-class molecules is an imperative for next-generation antimalarials.

NVP-INE963 is an oral, fast-acting blood-stage antimalarial candidate from the long-standing Novartis/MMV collaboration aiming for a single dose cure for P. falciparum malaria.

The starting point for the molecule was identified using a phenotypic HTS, and although a mechanism of action has yet to be identified for the molecule, its activity against multidrug-resistant P. falciparum cell lines and demonstration of high barrier to resistance are suggestive of polypharmacology.

Preliminary Ph. 2 results shared at the ACS Spring 2026 meeting by Chris Sarko showed single-dose NVP-INE963 was curative at five days post-dose, which was maintained beyond 60 days in patients with uncomplicated P. falciparum malaria.

Read more on Drug Hunter: https://drughunters.com/4uJmqXT