Minipigs have recently gained prominence as an alternative non-rodent in vivo model for pharmacokinetic (PK), efficacy, and toxicology studies supporting human dose predictions. This article provides an overview of the use of minipigs in small molecule preclinical drug discovery research, tracing their historical background and outlining practical considerations for selecting them in studies focusing on hepatic metabolism, oral bioavailability, CNS penetration, and toxicology. It highlights minipigs' unique advantages and makes a compelling case for their continued use in preclinical research.

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.

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

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)

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... [...]

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 [...]

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 [...]