Computationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia

The permeability
glycoprotein, encoded by the ABCB1 gene, is widely
implicated in multidrug resistance (MDR), as it
has been shown to reduce the intracellular concentration of most small
molecule therapeutics, including the majority of the breakpoint cluster
region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used
in the treatment of Philadelphia chromosome positive (Ph+) leukemias.
With this in mind, we describe an integrated theoretical and experimental
approach to shed light on substituent effects in the pendant anilino
moiety of 4-anilino­quinazolines and 4-anilino­quinoline-3-carbonitrile-based
kinase inhibitors and their influence on P-gp-mediated efflux. This
analysis culminated in the identification of a hydroxyl­amine-bearing,
dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits
a marked reduction in P-gp-mediated efflux ratio and potent activity
in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived
cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate
that the P-gp-mediated efflux ratio can be minimized by computationally
driven optimization of the molecular dipole and/or cpKa without recourse to intramolecular hydrogen bonds.