# Inhibition of Bcl-xL by Targeted Degradation

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $505,715

## Abstract

Targeting the anti-apoptotic Bcl-2 family proteins is a promising therapeutic strategy for cancer and has been
validated by the FDA approval of the Bcl-2 selective inhibitor, venetoclax, for the treatment of chronic lymphocytic
leukemia (CLL) and acute myeloid leukemia (AML). Given the well-documented importance of Bcl-xL to many
types of cancers, including most T-cell acute lymphoblastic leukemia (T-ALL), and its contribution to drug
resistance, Bcl-xL has become one of the best validated cancer targets. Unfortunately, the on-target and dose-
limiting platelet toxicity associated with the inhibition of Bcl-xL has prevented the use of Bcl-xL inhibitors in the
clinic. To circumvent this toxicity, we have applied the Proteolysis Targeting Chimera (PROTAC) technology to
design small-molecules that target Bcl-xL to E3 ligases for degradation. Our hypothesis is that Bcl-xL degrading
PROTACs (named as Bcl-Ps) designed to recruit an E3 ligase that is minimally expressed in platelets for the
targeted degradation of Bcl-xL will have reduced platelet toxicity and improved antitumor activity compared with
their corresponding Bcl-xL inhibitors. This hypothesis is supported by our strong preliminary results, including in
vivo efficacy data in T-ALL patient-derived xenograft (PDX) mouse models and other tumor xenograft mouse
models. In addition, our Bcl-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs),
because SnCs also rely on Bcl-xL for survival. Clearance of chemotherapy-induced SnCs is considered as a
novel strategy to prevent or reduce many short- and long-term adverse effects of the chemotherapeutic drugs,
as well as cancer relapse and metastasis. Collectively, these findings suggest that Bcl-Ps are superior to
conventional Bcl-xL inhibitors as anticancer agents. The goal of this application is to: (1) optimize Bcl-Ps for
improved potency, selectivity, drug-like properties, and in vivo efficacy; (2) evaluate the new Bcl-Ps through a
series of in vitro and in vivo assays; and (3) evaluate the preclinical efficacy of lead Bcl-Ps in T-ALL PDX models.
Upon completion of this project, we aim to produce Bcl-Ps amenable to further evaluation in clinical trials for T-
ALL, an aggressive leukemia that currently has no targeted therapies.

## Key facts

- **NIH application ID:** 10133018
- **Project number:** 5R01CA241191-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Marina Y Konopleva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $505,715
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133018

## Citation

> US National Institutes of Health, RePORTER application 10133018, Inhibition of Bcl-xL by Targeted Degradation (5R01CA241191-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133018. Licensed CC0.

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