Discovery of selective and noncovalent diaminopyrimidine-based inhibitors of epidermal growth factor receptor containing the T790M resistance mutation.
Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.
Departments of †Discovery Chemistry, ‡Structural Biology, §Drug Metabolism and Pharmacokinetics, ∥Biochemical and Cellular Pharmacology, ⊥Molecular Oncology, and #Protein Expression, Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Emily J
EJ
Hanan
Charles
C
Eigenbrot
Marian C
MC
Bryan
Daniel J
DJ
Burdick
Bryan K
BK
Chan
Yuan
Y
Chen
Jennafer
J
Dotson
Robert A
RA
Heald
Philip S
PS
Jackson
Hank
H
La
Michael D
MD
Lainchbury
Shiva
S
Malek
Hans E
HE
Purkey
Gabriele
G
Schaefer
Stephen
S
Schmidt
Eileen M
EM
Seward
Steve
S
Sideris
Christine
C
Tam
Shumei
S
Wang
Siew Kuen
SK
Yeap
Ivana
I
Yen
Jianping
J
Yin
Christine
C
Yu
Inna
I
Zilberleyb
Timothy P
TP
Heffron
D019943:Amino Acid Substitution; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008715:Methionine / Q000235:genetics; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use; D013912:Threonine / Q000235:genetics
D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D013912:Threonine; D008715:Methionine; D066246:ErbB Receptors