451. Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946).
- Author
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Scott WJ, Hentemann MF, Rowley RB, Bull CO, Jenkins S, Bullion AM, Johnson J, Redman A, Robbins AH, Esler W, Fracasso RP, Garrison T, Hamilton M, Michels M, Wood JE, Wilkie DP, Xiao H, Levy J, Stasik E, Liu N, Schaefer M, Brands M, and Lefranc J
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Binding Sites, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class Ib Phosphatidylinositol 3-Kinase chemistry, Drug Discovery, Humans, Hydrogen Bonding, Imidazoles chemical synthesis, Imidazoles chemistry, Molecular Docking Simulation, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrimidines chemical synthesis, Pyrimidines chemistry, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, Imidazoles pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Quinazolines pharmacology
- Abstract
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., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
- Published
- 2016
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