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

Abstract

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.

• Authors: Meredith S Eno, Jason D Brubaker, John E Campbell, Chris De Savi, Timothy J Guzi, Brett D Williams, Douglas Wilson, Kevin Wilson, Natasja Brooijmans, Joseph Kim, Ayşegül Özen, Emanuele Perola, John Hsieh, Victoria Brown, Kristina Fetalvero, Andrew Garner, Zhuo Zhang, Faith Stevison, Rich Woessner, Jatinder Singh, Yoav Timsit, Caitlin Kinkema, Clare Medendorp, Christopher Lee, Faris Albayya, Alena Zalutskaya, Stefanie Schalm, Thomas A Dineen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 14 Pg. 9662-9677 (07 28 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35838760 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Drug Resistance, Neoplasm
• ErbB Receptors
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)