Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361)

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.