Drug Hunter, Palo Alto, CA (2026)

03/13/2026

2025 Molecule of the Year Nominees | https://drughunters.com/4ryC4ng

Each year, we ask the drug discovery community to nominate the molecules you found most technically impressive and impactful in 2025.

Here is the final list of the top 10 nominees for the 2025 Molecule of the Year, selected by our readers and reviewers.

These finalists are selected based on technical achievement, scientific contribution, potential clinical impact, and novelty, among other factors.

The 2025 Molecule of the Year nominees include:

- orforglipron (OWL833) – oral GLP-1 receptor partial agonist from Chugai and Eli Lilly
- daraxonrasib (RMC-6236) – oral pan-RAS(ON) inhibitor from Revolution Medicines
- oveporexton (TAK-861) – oral OX2R agonist from Takeda
- rilzabrutinib (PRN1008) – oral, reversibly covalent BTK inhibitor from Principia / Sanofi
- icotrokinra (JNJ-2113) – oral IL-23 receptor peptide antagonist from Protagonist Therapeutics and Johnson & Johnson
- votoplam (PTC518) – oral HTT mRNA splice modulator from PTC Therapeutics and Novartis
- aficamten (CK-3773274) – oral cardiac myosin inhibitor from Cytokinetics
- nerandomilast (BI 1015550) – oral preferential PDE4B inhibitor from Boehringer Ingelheim
- vepdegestrant (ARV-471) – oral PROTAC ER degrader from Arvinas and Pfizer
- zolucatetide (FOG-001) – IV β-catenin:TCF PPI inhibitor from Parabilis Medicines

Read more about these molecules and vote for your favorite here: https://drughunters.com/4ryC4ng

03/13/2026

New Series on Drug Hunter: Classics in Drug Discovery

Revisit the molecules that defined an era—whether by validating a target, inventing a modality, or changing how trials (and endpoints) get run.

The first installment drops soon. Any guesses on the first molecule? Here’s a hint: it helped pull “targeted therapy” into the spotlight—and reshaped how we measure clinical response.

Drop your “classic” molecule picks in the comments—and why they belong (breakthrough biology, ingenious chemistry, surprising clinical strategy, etc.). Bonus points for a must-read paper.

Stay tuned!

03/12/2026

Beyond the Pill: Why Nasal Delivery Offers Unique Opportunities | https://drughunters.com/40ZUoKW

While tablets remain the default for small molecule delivery, the intranasal route offers compelling advantages worth considering early in program design. This review covers the practical case for nasal delivery, including:

-The breadth of indications that have utilized nasal delivery from esketamine (Spravato®) for treatment-resistant depression, to glucagon (Baqsimi®) for severe hypoglycemia
-Direct CNS access via the olfactory bulb and trigeminal nerve, bypassing the blood–brain barrier
-Dose-sparing benefits of intranasal administration, which is especially valuable when API is scarce in early development
-Formulation strategies like shear-thinning liquid sprays and dry powder systems
-Device options for research and emergency use settings
-Key limitations, such as compound potency requirements and mucosal enzymatic degradation

It may be time to think beyond the pill.

Read the full article on Drug Hunter: https://drughunters.com/40ZUoKW

03/12/2026

Discovery of a Small Molecule HPK1 Inhibitor for Immuno-Oncology
https://drughunters.com/4b4ksdU
Thursday, April 16th, 2026
8 AM PT | 11 AM ET | 5 PM CET

HPK1 is a negative regulator of T-cell signaling and has emerged as a promising new target in immuno-oncology, where selective inhibition can enhance T-cell-mediated tumor killing but requires careful optimization of kinase selectivity to avoid undesired immunosuppression.

In this Flash Talk, Rebecca Gallego, Associate Research Fellow at Pfizer, will highlight how lipophilic efficiency analysis and structure-based drug design guided optimization efforts leading to the discovery of PF-07265028, a potent and selective HPK1 inhibitor that advanced to a Phase 1 clinical trial. She will discuss how mechanistic cellular assays were used to quantify HPK1 inhibition, alongside functional assays and biochemical profiling to evaluate kinase selectivity and avoid key anti-targets.

If you are curious to learn more about the challenges of designing selective HPK1 inhibitors, sign up for this Flash Talk today: https://drughunters.com/4b4ksdU

03/11/2026

Remibrutinib: Occupancy-Driven BTK Inhibition Delivers Durable Efficacy in CSU | https://drughunters.com/4sZ3Haj

Remibrutinib (Rhapsido®) brings BTK inhibition into an “unusual” place: CSU (chronic spontaneous urticaria), where the efficacy requirements and long-term safety bars are high.

BTK sits downstream of FcεRI in mast cells/basophils, helping drive degranulation and histamine release, so BTK inhibition can blunt symptoms across different autoantibody triggers.

Phase 3 REMIX-1 (NCT05030311) / REMIX-2 (NCT05032157) in CSU uncontrolled by H1 antihistamines:
- 25 mg BID improved disease activity by week 1
- Week 52: ~62–63% achieved UAS7 ≤6; ~45–46% achieved UAS7 = 0
- Safety over 52 weeks was generally manageable (mostly mild/moderate AEs)

Read our coverage on remibrutinib, and how an occupancy-driven PD strategy translated into clinical efficacy.

Read the full article on Drug Hunter: https://drughunters.com/4sZ3Haj

03/10/2026

An Inhibitor of CBL-B for Immuno-oncology Indications | https://drughunters.com/4rHBvrr

NX-1607, the first orally bioavailable small molecule inhibitor of CBL-B from , has entered clinical trials for advanced malignancies.

CBL-B is an intracellular immune checkpoint critical for regulating immune activation in T, B, and NK cells. While immune checkpoint inhibitors like PD-1/PD-L1 have been effective for various cancers, they have limitations such as lack of efficacy in certain cancers, variability in patient responses, and the development of resistance.

NX-1607 locks the CBL-B protein in an inactive conformation, thereby enhancing T cell activation. In preclinical studies, NX-1607 demonstrated significant anti-tumor activity and improved long-term survival in murine models.

This article details the target rationale, discovery, characterization, and preclinical profile that qualified NX-1607 as the first small molecule CBL-B inhibitor to enter clinical trials. We also include the encouraging preliminary efficacy data released at ESMO 2025.

Read it on Drug Hunter: https://drughunters.com/4rHBvrr

03/10/2026

In this Flash Talk, Mark Murcko shared his view on importance of affinity in drug design, highlighting that affinity should be optimized rather than maximized.

Mark identified seven distinct advantages of this approach, including achieving greater potency, accelerating lead optimization, encouraging teams to pursue more challenging chemical matter, and avoiding the ""avoidome"" among others.

Mark also directly addressed potential objections to this approach such as focus on affinity may negatively impact other properties, the applicability of the concept to novel modalities, or to rather focus on toxicity issues. His thesis is that a focus on affinity can help overcome these challenges rather than cause them.

If you are interested in understanding the distinct advantage of an affinity-first approach, watch the full Flash Talk on our YouTube channel: https://drughunters.com/4rmxRmm
"

03/09/2026

Vornorexant Wins Japan Approval on a “Rapid-On/Rapid-Off” DORA Profile | https://drughunters.com/4b0IXJ4

Vornorexant (TS-142) is a dual orexin receptor antagonist (DORA; OX1R/OX2R) approved for insomnia in Japan in August 2025 as Vorzzz®.

With multiple DORAs already on the market, vornorexant’s key differentiator is pharmacokinetic: rapid absorption and a short half-life, aimed at minimizing next-day residual effects that can complicate hypnotic therapy.

A dedicated next-day function study put that thesis to the test—showing no clinically meaningful driving impairment ~9 hours post-dose versus placebo after single and repeated dosing.

In the pivotal Ph. 3 trial, 5 mg and 10 mg QD significantly improved sleep onset and sleep efficiency versus placebo, supporting approval.

Taisho has not publicly disclosed whether it plans to pursue US approval.

Read more on Drug Hunter: https://drughunters.com/4b0IXJ4

03/09/2026

Target Validation | https://drughunters.com/4lhG5uI

Target validation failures, due to an incomplete understanding of target biology or mechanism, are a leading cause of attrition in early stages of both research and development.

In this lecture, we highlight the utility of phenotypic drug discovery for identifying novel opportunities for disease intervention, which can serve as the basis for de novo drug discovery campagins.

We also introduce orthogonal approaches to biological validation using complementary tools – including chemical probes, ASKA, RNAi, and CRISPR – each of which offers distinct strengths and limitations for target validation.

03/06/2026

BTK Degraders Racing to Treat B-Cell Malignancies

The second half of 2025 saw clinical updates from two different BTK degraders seeking to change the future of patients with relapsed/refractory B-cell malignancies. This new application of targeted protein degradation hopes to overcome acquired resistance and offer a new lifeline to patients suffering from some of the most common hematological malignancies in the western world. Six companies are now pursuing clinical trials in this promising field, with the most advanced assets now in or about to enter pivotal phase 3 trials. Preliminary clinical data continue to support the viability of this strategy leaving us with the most important questions: will this be a win for patients and if so, who will be first and who will be best?

Read it on Drug Hunter | https://drughunters.com/4rdhngk

03/05/2026

Late 2025 brought a string of positive results for pirtobrutinib: traditional approval in BTK-resistant CLL/SLL, positive results from multiple Ph. 3 studies, and preliminary data from combination trials in B-cell malignancies.

This oral, noncovalent BTK inhibitor has demonstrated efficacy against malignancies that are resistant to covalent BTK inhibitors and improved safety profile in the clinic.

Pirtobrutinib is well-positioned to become a 1st-line therapeutic; however, competition is intense, and already new BTK inhibitors and degraders are going head-to-head with this drug in late-stage clinical trials.

Read it on Drug Hunter: https://drughunters.com/4bouB57

03/04/2026

First-time approvals of large molecule therapeutics continue to reshape the global medicines landscape, especially outside the US.

In our latest non-US approvals coverage, we reviewed first-time approvals from China’s NMPA and the EMA.

A few patterns stood out:
- Oncology leads the pack in total approvals
- Endocrinology follows closely, driven largely by GLP-1–based therapies
- Additional activity spans infectious diseases, metabolic disorders, and more

We also attach a poster that compiles key details across programs, including drug structures, dosing, indications, and the companies behind their discovery and development.

Read the full article: https://drughunters.com/4rPhUq5

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