1. Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361)
- Author
-
Johnson Y.N. Lau, Gerald J. Fetterly, Yahao Bu, Michael Smolinski, Irwin H. Gelman, Allen Barnett, Taher Hegab, David L. Cutler, David G. Hangauer, Jane W. S. Fang, Rudolf Kwan, and James L. Clements
- Subjects
0301 basic medicine ,Pyridines ,Morpholines ,Phases of clinical research ,Peptide ,03 medical and health sciences ,0302 clinical medicine ,Catalytic Domain ,Cell Line, Tumor ,Acetamides ,Drug Discovery ,medicine ,Humans ,Amino Acid Sequence ,Protein Kinase Inhibitors ,Peptide sequence ,chemistry.chemical_classification ,Drug discovery ,Tubulin Modulators ,Molecular Docking Simulation ,src-Family Kinases ,030104 developmental biology ,Mechanism of action ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,medicine.symptom ,Tyrosine kinase ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src - Abstract
The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA.
- Published
- 2018