# Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $433,304

## Abstract

PROJECT SUMMARY
Given the pivotal role of anti-apoptotic Bcl-2 family of proteins in cancer cell survival and resistance to
chemotherapy, the development of novel anti-cancer therapeutics targeting the BH3 binding groove of anti-
apoptotic Bcl-2 proteins have emerged as a promising, yet challenging therapeutic goal. The recent approval of
Venetoclax (ABT199), a selective Bcl-2 antagonist whose design and development spanned well over fifteen
years of iterative optimizations using extensive structure-based refinements, suggested that it is indeed possible,
albeit extremely challenging, to attain inhibitors of protein-protein interactions (PPIs) that are clinically
relevant. However, we and others found that overexpression of both Mcl-1 and, perhaps more relevant, Bfl-1
(two other members of the Bcl-2 family protein that are not targeted by Venetoclax), confer resistance to
chemotherapy and to Bcl-2 antagonists. Recent efforts from our laboratory identified possible novel routes to
design potent and selective inhibitors of PPIs targeting these oncogenes that encompass structure-based design
of covalent inhibitors. Hence, we propose to further investigate these innovative structure-guided drug discovery
strategies and to apply them to the design of potent dual Mcl-1/Bfl-1 antagonists. If successful, our studies could
result in general methods to target PPIs and could also identify innovative lead compounds for the treatment of
cancer.

## Key facts

- **NIH application ID:** 9885307
- **Project number:** 2R01CA168517-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Maurizio Pellecchia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,304
- **Award type:** 2
- **Project period:** 2012-07-09 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9885307

## Citation

> US National Institutes of Health, RePORTER application 9885307, Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach (2R01CA168517-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9885307. Licensed CC0.

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