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Rational design of Notch2 and ER-AF2 inhibitors as prospective bladder cancer and breast cancer therapies

University of British Columbia

Breast cancer (BCa) and Bladder Cancer (BdCa) are among the most predominantly diagnosed malignancies in women and men, respectively. The NOTCH signaling pathway is a targetable interest in developing effective therapy for BdCa while Estrogen Receptor α (ERα+) is still the most prominent drug target in BCa. It is well established however, that currently available options for Notch and ERα inhibition suffer from lack of selectivity. Thus, the two subtypes of ER - α and β have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. Moreover, long term conventional therapy of BCa induces resistance with an increased risk of endometrial cancer onset. Similarly, Notch proteins are highly conserved in structure but possess very diverse functionality, with Notch 1 being a tumor suppressor, while closely-related Notch 2 being an onco-driver in BdCa and its current targeting strategies results in adverse off-target effects. Thus, there is an urgent need to develop novel drugs with alternative targeting mechanisms that can overcome the limitations of conventional Notch2- and ERα-based therapies. With the help of Computer-Aided Drug Design (CADD) technology, we have discovered novel small molecules to target previously unattended AF2 site on ERα and the S2 site on Notch 2 to achieve the desired selectivity in inhibition while overcoming the conventional therapy’s caveats.

Text

2024-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75966

Bioinformatics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/