- 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
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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.
- Burke, Jason P.,Carroll, Christopher L.,Cross, Jason B.,Czako, Barbara,Di Francesco, Maria Emilia,Draetta, Giulio,Feng, Ningping,Harris, Angela L.,Heffernan, Timothy,Jiang, Yongying,Jones, Philip,Kang, Zhijun,Kohl, Nancy E.,Kovacs, Jeffrey J.,Leonard, Paul G.,Mandal, Pijus,Marszalek, Joseph. R.,McAfoos, Timothy,Meyers, Brooke A.,Mseeh, Faika,Parker, Connor A.,Sun, Yuting,Williams, Christopher C.,Wu, Qi,Yu, Simon S.
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p. 15141 - 15169
(2021/11/01)
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- HETEROARYL DERIVATIVES AS SEPIAPTERIN REDUCTASE INHIBITORS
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Inhibitors of sepiapterin reductase of formula (I) or (I'), wherein the substituents are defined as in the claims, and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.
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Paragraph 00402-00405
(2017/05/31)
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- HETEROCYCLIC INHIBITORS OF PTPN11
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The present invention relates to compounds which may be useful as inhibitors of PTPN11 for the treatment or prevention of cancer and other PTP-mediated diseases. The compounds are based on various substituted ring-fused pyrimidin-4-ones.
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Paragraph 0155-0157
(2017/09/27)
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- PYRAZOLOPYRIMIDONE AND PYRAZOLOPYRIDONE INHIBITORS OF TANKYRASE
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There are provided compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein Q, R1 and R2 are as defined herein. The compounds of formula I are useful in the treatment of cancer.
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Page/Page column 85; 86
(2014/01/08)
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