A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor.
Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.
From the Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Theonie
T
Anastassiadis
Krisna C
KC
Duong-Ly
Sean W
SW
Deacon
Alec
A
Lafontant
Haiching
H
Ma
Karthik
K
Devarajan
Roland L
RL
Dunbrack
Jinhua
J
Wu
Jeffrey R
JR
Peterson
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D010766:Phosphorylation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000145:classification; D011720:Pyrazoles / Q000737:chemistry; D011724:Pyridazines / Q000737:chemistry; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*
C505241:FR 180204; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D000255:Adenosine Triphosphate; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
ERK; Enzyme Inhibitors; High Throughput Screening (HTS); Insulin Receptor; Insulin-like Growth Factor 1 Receptor; Kinase Inhibitor; Receptor Tyrosine Kinase; Small-molecule Inhibition; X-ray Crystallography