Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.

Autor: Eno MS; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Brubaker JD; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Campbell JE; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., De Savi C; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Guzi TJ; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Williams BD; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Wilson D; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Wilson K; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Brooijmans N; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Kim J; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Özen A; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Perola E; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Hsieh J; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Brown V; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Fetalvero K; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Garner A; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Zhang Z; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Stevison F; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Woessner R; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Singh J; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Timsit Y; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Kinkema C; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Medendorp C; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Lee C; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Albayya F; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Zalutskaya A; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Schalm S; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States., Dineen TA; Blueprint Medicines, 45 Sidney Street, Cambridge, Massachusetts 02139, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Jul 28; Vol. 65 (14), pp. 9662-9677. Date of Electronic Publication: 2022 Jul 15.
DOI: 10.1021/acs.jmedchem.2c00704
Abstrakt: While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30 ) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.
Databáze: MEDLINE
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