2,4,6-Substituted Quinazolines with Extraordinary Inhibitory Potency toward ABCG2

Several members of the ABC transporter
superfamily play a decisive
role in the development of multidrug resistance (MDR) in cancer. One
of these MDR associated efflux transporters is ABCG2. One way to overcome
this MDR is the coadministration of potent inhibitors of ABCG2. In
this study, we identified novel inhibitors containing a 2,4,6-substituted
quinazoline scaffold. Introduction of a 6-nitro function led to extraordinarily
potent compounds that were highly selective for ABCG2 and also able
to reverse the MDR toward the chemotherapeutic drugs SN-38 and mitoxantrone.
The binding of substrate Hoechst 33342 and the two potent inhibitors 31 and 41 which differ in their mechanism of
inhibition was rationalized using the recently published cryo-EM structures
of ABCG2. For a better understanding of the interaction between the
inhibitors and ABCG2, additional investigations regarding the ATPase
activity, the interaction with Hoechst 33342, and with the conformational
sensitive 5D3 antibody were carried out.