Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor.

Abstract

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.

• Authors: Barbara Czako, Yuting Sun, Timothy McAfoos, Jason B Cross, Paul G Leonard, Jason P Burke, Christopher L Carroll, Ningping Feng, Angela L Harris, Yongying Jiang, Zhijun Kang, Jeffrey J Kovacs, Pijus Mandal, Brooke A Meyers, Faika Mseeh, Connor A Parker, Simon S Yu, Christopher C Williams, Qi Wu, Maria Emilia Di Francesco, Giulio Draetta, Timothy Heffernan, Joseph R Marszalek, Nancy E Kohl, Philip Jones
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 20 Pg. 15141-15169 (10 28 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34643390 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (administration & dosage, chemistry, pharmacology)
• Humans
• Mice
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship