A First-in-Class TRPA1 Antagonist Overcomes Toxicity Hurdles to Become Cough Candidate

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after preclinical studies and a Ph. I trial showed it was well-tolerated, in contrast to prior molecules. The transient receptor potential (TRP) family of ion channels has been the subject of intensive drug discovery efforts due to their critical role in the development and progression of pain, itch, and respiratory conditions.

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after pre...

More LRRK2 On-Target Toxicity?

LRRK2 has been a hotly pursued drug target for Parkinson’s Disease based on human genetics. Clinical advancement of LRRK2 inhibitors was initially stalled by concerns about on-target lung findings in primates, but these were ameliorated by a Merck/Genentech/Pfizer/MJFF study showing that these lung changes were reversible, and Biogen/Denali has currently a small molecule (BIIB122/DNL151) in Ph. II (NCT05348785) after demonstrating safety and CNS exposure in 145 healthy patients in Ph. I (NCT04557800)

LRRK2 has been a hotly pursued drug target for Parkinson’s Disease based on human genetics. Clinical advancement of LRRK2 inhibito...

DN-1289

DN-1289 is a CNS-penetrant, ATP-competitive DLK/LZK-selective dual kinase inhibitor intended to treat amyotrophic lateral sclerosis (ALS). The molecule is structurally closely related to Genentech’s recent Ph. I candidate, GDC-0134. Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are... [...]

DN-1289 is a CNS-penetrant, ATP-competitive DLK/LZK-selective dual kinase inhibitor intended to treat amyotrophic lateral sclerosi...

Drug Hunter Letters #2: On Carboxylic Acids and Acylglucuronides

Recently, Dr. Alf Claesson (CEO of Awametox AB, inventor of SpotRM, and previously Principal Scientist and Section Head at AstraZeneca/Astra AB, Sweden) reached out about our resource on the bioactivation of structural alerts . Dr. Claesson shared the helpful notes that: carboxylic acids forming thioesters with CoA might be a greater danger [...]

Recently, Dr. Alf Claesson (CEO of Awametox AB, inventor of SpotRM, and previously Principal Scientist and Section Head at AstraZe...

"compound 5"

The Genentech VPS34 kinase inhibitor, compound 5, is a selective kinase inhibitor that is unusually polar for a kinase inhibitor (logD = 1.0, PPB = 23%) but maintains low clearance. The article was nominated by reviewers Joachim Rudolph, Callie Bryan, Christian Kuttruff, and Julien Lefranc for its interesting tricyclic structure and [...]

The Genentech VPS34 kinase inhibitor, compound 5, is a selective kinase inhibitor that is unusually polar for a kinase inhibitor (...