Mcl-1 and the E3 ligase HDM2 are two oncoproteins that are overexpressed in, and directly contribute to, multiple human cancers, including acute myeloid leukemia (AML) and multiple myeloma (MM). In the quest for new treatments for hematological malignancies, there are several on-going clinical trials for Mcl-1 inhibitors, such as AZD5991 and S63845, and also for the HDM2 inhibitor idasanutlin. Since cancer is a multi-factorial disease, the most curative treatments typically involve cocktails of drugs rather than single target, highly-selective drugs. However, combination therapies are often associated with drawbacks, such as side effects, complicated drug-drug interactions and poor patient compliance. Rationally designed dual target inhibitors provides an alternative strategy to combination therapies; such polypharmacology may elicit superior efficacy owing to concomitant inhibition of both targets in the same tissue, is devoid of drug-drug interactions, and may furnish improved patient compliance. Accordingly, we have recently developed dual Mcl-1/HDM2 inhibitors through rational design of a single pharmacophore capable of recognizing both proteins. The present research focuses on the merging of two pharmacophores – one that recognizes Mcl-1 and the other that recognizes HDM2 – to afford bivalent inhibitors. PROteolysis TArgeting Chimera, or PROTAC, technology is an emerging approach to discover new clinical candidates that operate by a novel therapeutic paradigm, that is by targeted protein degradation. PROTACs are also bivalent inhibitors wherein the ligand of interest is merged to a pharmacophore that is recognized by an E3 ligase. The ligand’s protein is recruited to the ligase, then polyubiquitinated and subsequently degraded by the ubiquitin-protease system. Therefore, since HDM2 is an E3 ligase, it is hypothesized that bivalent Mcl-1/HDM2 inhibitors will inherently function as PROTACs as well. We will present our progress towards first-in-class dual Mcl-1/HDM2 PROTACs, including their evaluation in AML and MM cancer cell lines.

Towards first-in-class dual Mcl-1/HDM2 PROTACs to treat hematological malignancies

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.