New Inhibitors of Breast Cancer Resistance Protein (ABCG2) Containing a 2,4-Disubstituted Pyridopyrimidine Scaffold

Multidrug
resistance (MDR) occurring during cancer chemotherapy
is a major obstacle for effectiveness and response to therapy and
is often caused by ATP-binding cassette (ABC) efflux transporters.
Belonging to the family of ABC transporters, breast cancer resistance
protein is getting more and more in the spotlight of research. As
a strategy to overcome MDR, inhibitors of ABC transporters were synthesized,
which could be applied in combination with cytostatic drugs. For this
purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized.
The investigations confirmed three key characteristics of good inhibitors:
a low intrinsic cytotoxicity and a high potency and selectivity toward
ABCG2. For selected compounds the interaction with ABCG2 was elucidated
and their effect on ATPase activity and conformation sensitive 5D3
antibody binding was investigated. Their ability to reverse MDR in
coadministration with the active metabolite of irinotecan and mitoxantron
was confirmed.