Drug Hunter, Palo Alto, CA (2025)

09/02/2025

Zongertinib: A Covalent, Brain-Penetrant HER2-Selective TKI for HER2-Mutant nSCLC Gets FDA Approval | https://drughunters.com/3I4dwBE

Zongertinib (Hernexeos®, BI 1810631) is a covalent, HER2-selective TKI approved by the FDA in August 2025 for patients with unresectable or metastatic non-squamous nSCLC.

The Boehringer compound is designed to spare fellow ErbB family protein EGFR, offering a precision approach for HER2-mutant nSCLC—a subset historically underserved due to the limitations of existing HER2 TKIs.

Zongertinib’s approval underscores its promising potential in the HER2-mutant nSCLC landscape—and a possible “pipeline in a product” for Boehringer Ingelheim.

Read it on Drug Hunter: https://drughunters.com/3I4dwBE

09/02/2025

In this Flash Talk, Mark Murcko outlines a vision for tackling one of the hardest challenges in drug discovery: interactions with anti-targets.

Mark introduces the concept of the "avoidome", a collection of proteins involved in ADME, transport, and toxicity (such as CYP, p-gp, and hERG). Binding and activity on these proteins often derail promising compounds despite strong on-target activity.

Drawing on lessons from his career, he illustrates how anti-target interactions have halted progress and why target affinity alone is insufficient. Mark emphasizes the importance of multi-parameter optimization and shares a framework for how an interdisciplinary team of scientists could systematically tackle avoidome liabilities. A key element of this vision is the generation of large-scale, high-quality, publically availble data on avoidome targets to enable predictive modeling of anti-target interactions.

He encourages drug discovery teams and particularly structural biologists to embrace the structural complexity of avoid-ome proteins. With a concerted effort to understand structure and dynamics, reduce assay costs, and develop better predictive models for avoidome targets, drug discovery at large could make a huge leap forward!

If you're working in preclinical drug discovery, this talk is a must-watch!

Watch the full Flash Talk on our YouTube channel: https://drughunters.com/47PpWI7

09/01/2025

From Molecular Properties to Mechanistic ADME: A Guide to Scoring Success
https://drughunters.com/4lV8yFx
Thursday, October 2nd, 2025
8 AM PT / 11 AM ET / 5 PM CET

Optimizing small molecules in drug discovery is a complex, multifactorial problem that requires distilling vast in silico, in vitro, and in vivo data while balancing multiple properties to guide compound progression.

In this Flash Talk, Fabio Broccatelli, head of DMPK and Computational Chemistry at Altos Labs, will present novel approaches that leverage PBPK (physiologically based pharmacokinetic) modeling, machine learning, and physicochemical properties to score and prioritize compounds effectively.

He will introduce the BPI (Balanced Permeability Index) for predicting permeability, share workflows for prioritizing compounds for synthesis and in vivo testing, and show how these strategies accelerate discovery while reducing reliance on animal studies.

Sign up now to learn about the current state of the art, its limitations, and potential strategies to overcome them: https://drughunters.com/46kT9Zp

08/30/2025

Opposing Views of the Immunology Target NEK7 | https://drughunters.com/45Y4BcY

NEK7 has emerged as a potentially complementary target to NLRP3 in inflammasome biology, with Halia’s allosteric inhibitor ofirnoflast (HT-6184) advancing into Ph. 2 in multiple indications, and Monte Rosa’s molecular glue degrader, MT-8102, cleared for Ph. 1 studies for gout.

However, a recent report from Novartis suggests NEK7 is not universally required for IL-1β release, raising questions about its role and the ultimate therapeutic value of NEK7-directed drugs.

Read it on Drug Hunter: https://drughunters.com/45Y4BcY

08/29/2025

Avapritinib (BLU-285), the Molecule Behind Sanofi’s $9B+ Acquisition of Blueprint Medicines | https://drughunters.com/3USCGpY

Sanofi opened their wallet this summer to acquire Blueprint Medicines and their pipeline of precision medicine small molecules in a deal worth over $9B in cash, their largest acquisition in nearly a decade.

The pipeline Sanofi has acquired in this deal includes a variety of small molecule immunology and oncology programs; however, the main attraction was certainly avapritinib (Ayvakit®) , an FDA-approved oral small molecule inhibitor of mutant KIT(D816V) and the homologous PDGFRɑ(D842V).

Avapritinib first gained FDA approval for treating GIST in 2020, but its more recent approvals in advanced and indolent forms of systemic mastocytosis appear to have been what attracted Sanofi.

This case study will examine how avapritinib has expanded treatment options for patients, the competitive landscapes emerging around this molecule, and what else Blueprint has cooking that may benefit Sanofi down the road.

Read it on Drug Hunter: https://drughunters.com/3USCGpY

08/29/2025

RBM39: A Second Wave of Molecular Glue Degraders | https://drughunters.com/4n2ga9Q

RBM39 molecular glue degraders are re-emerging as compelling molecules due to their ability to inhibit the role of RBM39 in both pre-mRNA splicing and transcriptional regulation, particularly in ER-driven cancers.

While first-generation degraders such as indisulam and tasisulam were discovered phenotypically, with their mechanism of action uncovered only after clinical failure. New second-generation degraders were rationally designed, with improved potency and selectivity:

- SEED Therapeutics’ ST-01156 (IND cleared, Ph.1 in 2026) targeting Ewing-sarcoma
- Recursion’s REC-1245 (Ph.1/2 ongoing)

The evolution of RBM39 molecular glue degraders from phenotypic discovery to rationally designed compounds highlights that mechanistic insight can reshape drug discovery strategies. However, upcoming clinical data will reveal whether the advances in design will translate into durable efficacy.

Read it on Drug Hunter: https://drughunters.com/4n2ga9Q

08/28/2025

Disclosures You’ll Want to See Before Your Next Design Meeting | https://drughunters.com/4g0KUWQ
Tuesday, September 2nd, 2025
8 AM PT | 11 AM ET | 5 PM CET

May it be an uncommon structural motif, an unusual mechanism of action, or a clever assay strategy, there are some Disclosures You’ll Want to See Before Your Next Design Meeting. In this meeting, we will show you how you can use Drug Hunter to stay on top of disclosures from the literature, conferences, and everything else in the drug discovery world.

While advancing your projects is likely your top priority, you don’t want to lose sight of strategies used on projects across the industry. Insights from other campaigns can sharpen your drug discovery knowledge and even sometimes spark immediate ideas for one of your projects. To help you stay informed without spending hours on conference reports and literature search, we distill the most important disclosures for you every month. Join us to see how you can use Drug Hunter as your go-to knowledge base.

Register here: https://drughunters.com/4g0KUWQ

08/28/2025

MD-4251 Is The First Orally Efficacious MDM2 Heterobifunctional Degrader | https://drughunters.com/45PnxKT

MDM2 is a target with potential impact on 50% of cancer patients. In a protein-protein interaction with wild-type p53, it inhibits the latter’s natural tumor suppressive properties.

For more than 20 years, MDM2 inhibitors thus far have failed to progress in clinical trials because of limited efficacy and safety issues.

MD-4251 represents the first orally efficacious heterobifunctional MDM2 degrader. After a single oral dose (50 mg/kg), RS4;11 xenograft mice show no detectable tumors for 24 days after complete regression.

Along with efficacy, there is no evidence of inducing thrombocytopenia in a mouse model, which provides hope for elimination of a key clinical toxicity signal.

Read it on Drug Hunter | https://drughunters.com/45PnxKT

08/27/2025

July 2025 Patent Highlights | https://drughunters.com/41S7J96

This month’s roundup of the patent literature features a variety of molecular scaffolds, targets, and strategies. From small phosphoramidic acid prodrugs that enhance solubility to macrocycle scaffolds with improved PK, the filings we cover include a number of broadly applicable strategies for drug hunters, as well as some hot new targets.

Highlights include:

- Scenic Biotech's PLA2G15 inhibitors for neurodegenerative diseases
- GSK's DNMT1 inhibitors for oncology and hematological diseases
- Ventus Therapeutics' CNS-penetrant NLRP3 inflammasome inhibitors for Parkinson’s disease and other CNS indications
- Xizang/Haisco’s PARP1-selective degraders for oncology
- Insilico Medicine's GLP-1R agonists for type 2 diabetes and obesity

Read it on Drug Hunter: https://drughunters.com/41S7J96

08/27/2025

DPP1 inhibitor Brensocatib Opens the Door for Neutrophil-Modulating Drugs with FDA Approval | https://drughunters.com/4oV2hfA

Brensocatib is an oral, reversible covalent, small molecule inhibitor of DPP1, recently approved by the FDA for the treatment of non-cystic fibrosis bronchiectasis—a severe, underdiagnosed chronic lung disease with no approved therapies.

With this approval, brensocatib is now the first-ever approved DPP1 inhibitor, and the first drug to receive regulatory approval for this debilitating condition.
Discovered by AstraZeneca and acquired by Insmed in 2016, brensocatib’s success reflects a breakthrough in targeting neutrophil-driven inflammation without triggering immunosuppression or dose-limiting toxicities.

Its reversible covalent warhead was rationally designed to inhibit DPP1 with just the right level of engagement—enough to durably reduce activation of NSPs, but without completely shutting down the pathway.

Read it on Drug Hunter: https://drughunters.com/4oV2hfA

08/26/2025

We’ve just made the Recent Disclosure Database even more valuable.

In addition to the recently added structures, Drug Hunter scientists now add annotation to notable molecules — giving you deeper context on emerging chemical matter from the latest literature, conferences, and more.

With these insights, you can:
- Stay up to date on recent disclosures in minutes without feeling overwhelmed
- Follow industry trends across targets, indications, and chemical matter
- Get inspired by the latest innovations in drug discovery

Explore the updated database and check out the annotations for yourself: https://drughunters.com/3Vk5XtD

08/26/2025

📣Reminder
Lessons in LAI: Discovery of a Long-Acting Injectable TAK1 Inhibitor
https://drughunters.com/4mxu6sC
Thursday, September 4th, 2025
8 AM PT / 11 AM ET / 5 PM CET

The global LAI (long acting injectable) market is projected to exceed USD 50 billion by 2034.

Join us for this Flash Talk with Jean-Baptiste Langlois and Thomas Ullrich, who will discuss why LAIs are gaining momentum in drug discovery.

In this presentation, they will present the key properties of small molecules suited for LAI formulations, the importance of early R&D collaboration, and share the discovery story of TAK-756, a potent, selective TAK1 inhibitor developed as a long-acting microcrystal suspension for intra-articular injection in OA (osteoarthritis).

Don’t miss this opportunity to learn key lessons on how drug molecules can be designed to facilitate formulation development in later stages of LAI projects.

Sign up here: https://drughunters.com/4fVxz1U"

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