# Novel Mcl-1 inhibitors for overcoming therapeutic resistance in colorectal cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $516,652

## Abstract

PROJECT SUMMARY/ABSTRACT
 Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US. Most CRCs either are
inherently insensitive to therapeutic treatment or acquire resistance upon relapse. Intrinsic and acquired
therapeutic resistance is one of the most significant obstacles in the treatment of CRCs. Mcl-1, a pro-survival
Bcl-2 family protein, has recently emerged as a key mediator of therapeutic resistance of CRCs. However, none
of the previously described Mcl-1 inhibitors are suitable for clinical development owing to insufficient in vivo
efficacy or undesirable pharmacokinetic properties. Utilizing integrated screening approaches and
structure-based design, we have recently developed a new class of Mcl-1 inhibitors with novel chemical
structures. The lead compound, 483, is highly selective for Mcl-1 and has potent activity against Mcl-1-mediated
drug resistance in CRC cells. It also exhibited promising pharmacological properties and completely overcame
Mcl-1-mediated drug resistance in vivo. Based on these findings, we propose to test the hypothesis that the 483
class of Mcl-1 inhibitors can be further developed to improve CRC therapy by targeting drug-resistant CRC cells.
Aim 1: Design and synthesis of novel Mcl-1 inhibitors with improved activity and properties; Aim 2: Biophysical,
biochemical, structural and functional characterization of novel Mcl-1 inhibitors; Aim 3: Determine the efficacy
and mechanism of action of novel Mcl-1 inhibitors in CRC cells; Aim 4. Analyze the pharmacological properties
and in vivo efficacy of novel Mcl-1 inhibitors. These studies may provide a major advance towards our long-term
goal of developing a novel class of therapy for human cancer by targeting Mcl-1.

## Key facts

- **NIH application ID:** 10149253
- **Project number:** 5R01CA217141-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Zaneta Nikolovska-Coleska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $516,652
- **Award type:** 5
- **Project period:** 2017-06-05 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149253

## Citation

> US National Institutes of Health, RePORTER application 10149253, Novel Mcl-1 inhibitors for overcoming therapeutic resistance in colorectal cancer (5R01CA217141-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149253. Licensed CC0.

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