In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing.
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.
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California rtjin@celgene.com.
Robert
R
Tjin Tham Sjin
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Kwangho
K
Lee
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Annette O
AO
Walter
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Aleksandr
A
Dubrovskiy
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Michael
M
Sheets
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Thia St
TS
Martin
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Matthew T
MT
Labenski
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Zhendong
Z
Zhu
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Richland
R
Tester
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Russell
R
Karp
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Aravind
A
Medikonda
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Prasoon
P
Chaturvedi
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Yixuan
Y
Ren
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Henry
H
Haringsma
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Jeff
J
Etter
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Mitch
M
Raponi
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Andrew D
AD
Simmons
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Thomas C
TC
Harding
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Deqiang
D
Niu
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Mariana
M
Nacht
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
William F
WF
Westlin
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Russell C
RC
Petter
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Andrew
A
Allen
Authors' Affiliations: Celgene Avilomics Research, Bedford, Massachusetts; and Clovis Oncology Inc., San Francisco, California.
Juswinder
J
Singh
D015761:4-Aminopyridine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
C026805:2,4-diaminopyridine; D015761:4-Aminopyridine; C512478:EGFR protein, human; D066246:ErbB Receptors