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In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing.

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Author information

Affiliations

  • 1. Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California
      Authors
    • Tjin Tham Sjin R 1
    (1 author)
  • 2. Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
      Authors
    • Lee K 2
    • Walter AO 2
    • Dubrovskiy A 2
    • Sheets M 2
    • Martin TS 2
    • Labenski MT 2
    • Zhu Z 2
    • Tester R 2
    • Karp R 2
    • Medikonda A 2
    • Chaturvedi P 2
    • Ren Y 2
    • Haringsma H 2
    • Etter J 2
    • Raponi M 2
    • Simmons AD 2
    • Harding TC 2
    • Niu D 2
    • Nacht M 2
    • Westlin WF 2
    • Petter RC 2
    • Allen A 2
    • Singh J 2
    (23 authors)

Molecular Cancer Therapeutics, 10 Apr 2014, 13(6):1468-1479
https://doi.org/10.1158/1535-7163.mct-13-0966 PMID: 24723450 

Abstract 

Patients with non-small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFR(WT)). These inhibitors have not provided compelling clinical benefit in T790M-positive patients, apparently because of dose-limiting toxicities associated with inhibition of EGFR(WT). Thus, there is an urgent clinical need for therapeutics that overcome T790M drug resistance while sparing EGFR(WT). Here, we describe a lead optimization program that led to the discovery of four potent irreversible 2,4-diaminopyrimidine compounds that are EGFR mutant (EGFR(mut)) selective and have been designed to have low affinity for EGFR(WT). Pharmacokinetic and pharmacodynamic studies in H1975 tumor-bearing mice showed that exposure was dose proportional resulting in dose-dependent EGFR modulation. Importantly, evaluation of normal lung tissue from the same animals showed no inhibition of EGFR(WT). Of all the compounds tested, compound 3 displayed the best efficacy in EGFR(L858R/T790M)-driven tumors. Compound 3, now renamed CO-1686, is currently in a phase I/II clinical trial in patients with EGFR(mut)-advanced NSCLC that have received prior EGFR-directed therapy.

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Read article at publisher's site: https://doi.org/10.1158/1535-7163.mct-13-0966

Read article for free, from open access legal sources, via Unpaywall: https://figshare.com/articles/journal_contribution/Supplementary_Materials_and_Methods_and_Supplementary_Figure_Legends_from_i_In_Vitro_i_and_i_In_Vivo_i_Characterization_of_Irreversible_Mutant-Selective_EGFR_Inhibitors_That_Are_Wild-Type_Sparing/22500922/1/files/39960208.pdfUnpaywall

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