2. Academic Validation
  3. Discovery of 6-[(3 S,4 S)-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

Discovery of 6-[(3 S,4 S)-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

  • J Med Chem. 2021 Oct 28;64(20):15141-15169. doi: 10.1021/acs.jmedchem.1c01132.
Barbara Czako 1,  Yuting Sun 2,  Timothy McAfoos 1,  Jason B Cross 1,  Paul G Leonard 1,  Jason P Burke 1,  Christopher L Carroll 1,  Ningping Feng 2,  Angela L Harris 2,  Yongying Jiang 1,  Zhijun Kang 1,  Jeffrey J Kovacs 2,  Pijus Mandal 1,  Brooke A Meyers 2,  Faika Mseeh 1,  Connor A Parker 1,  Simon S Yu 1,  Christopher C Williams 1,  Qi Wu 1,  Maria Emilia Di Francesco 1,  Giulio Draetta 3,  Timothy Heffernan 2,  Joseph R Marszalek 2,  Nancy E Kohl 4,  Philip Jones 1
Affiliations

Affiliations

  • 1 IACS (Institute for Applied Cancer Science), University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
  • 2 TRACTION (Translational Research to AdvanCe Therapeutics and Innovation in Oncology) University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
  • 3 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 4 Navire Inc., 421 Kipling Street, Palo Alto, California 94301, United States.
PMID: 34643390 DOI: 10.1021/acs.jmedchem.1c01132
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.

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