Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946).
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.
Global Development, Global Program Management, Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, 07981, USA. william.scott@bayer.com.
William J
WJ
Scott
Former Bayer Research Center, West Haven, CT, 16516, USA.
Martin F
MF
Hentemann
Former Bayer Research Center, West Haven, CT, 16516, USA.
R Bruce
RB
Rowley
Former Bayer Research Center, West Haven, CT, 16516, USA.
Cathy O
CO
Bull
Former Bayer Research Center, West Haven, CT, 16516, USA.
Susan
S
Jenkins
Former Bayer Research Center, West Haven, CT, 16516, USA.
Ann M
AM
Bullion
Former Bayer Research Center, West Haven, CT, 16516, USA.
Jeffrey
J
Johnson
Former Bayer Research Center, West Haven, CT, 16516, USA.
Anikó
A
Redman
Former Bayer Research Center, West Haven, CT, 16516, USA.
Arthur H
AH
Robbins
Former Bayer Research Center, West Haven, CT, 16516, USA.
William
W
Esler
Former Bayer Research Center, West Haven, CT, 16516, USA.
R Paul
RP
Fracasso
Former Bayer Research Center, West Haven, CT, 16516, USA.
Timothy
T
Garrison
Former Bayer Research Center, West Haven, CT, 16516, USA.
Mark
M
Hamilton
Global Drug Discovery, Project Management Drug Discovery, Bayer Pharma AG, 13353, Berlin, Germany.
Martin
M
Michels
Former Bayer Research Center, West Haven, CT, 16516, USA.
Jill E
JE
Wood
Former Bayer Research Center, West Haven, CT, 16516, USA.
Dean P
DP
Wilkie
Former Bayer Research Center, West Haven, CT, 16516, USA.
Hong
H
Xiao
Former Bayer Research Center, West Haven, CT, 16516, USA.
Joan
J
Levy
Global Drug Discovery, TRG Oncology, Bayer Pharma AG, 13353, Berlin, Germany.
Enrico
E
Stasik
Global Drug Discovery, TRG Oncology, Bayer Pharma AG, 13353, Berlin, Germany.
Ningshu
N
Liu
Global Drug Discovery, Structural Biology, Bayer Pharma AG, 13353, Berlin, Germany.
Martina
M
Schaefer
Global Drug Discovery, Medicinal Chemistry Berlin, Bayer Pharma AG, 13353, Berlin, Germany.
Michael
M
Brands
Global Drug Discovery, Medicinal Chemistry Berlin, Bayer Pharma AG, 13353, Berlin, Germany. julien.lefranc@bayer.com.
Julien
J
Lefranc
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human; C486018:PIK3CD protein, human; C546760:PIK3CG protein, human; C000589253:copanlisib
PI3K inhibitors; X-ray crystallography; copanlisib; lipid kinases; phosphoinositide 3-kinase