Protein-protein interactions (PPIs) govern key processes within the cell, including proliferation, differentiation, and cell death. The Bcl-2 protein family, which includes anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1 and Bcl-w, and their binding partners pro-apoptotic proteins Bim, Bad, Bak, and Bax, among others, are key regulators of the intrinsic apoptosis pathway. Dysregulation of these PPIs, which is often caused by upregulation of pro-apoptotic proteins, can lead to cell immortality and cancer. Tumor suppressor protein p53, which is involved in regulating numerous cell processes including apoptosis and senescence, is negatively regulated by its E3 ubiquitin ligase HDM2, which is often overexpressed in numerous cancers. There is cross-talk between these two protein families, with p53 a regulator of the Bcl-2 family via its transcription-independent apoptosis pathway during mitochondrial translocation. The Mcl1/Bim and HDM2/p53 interactions are governed by α-helices, with the PPI helical domains of Bim and p53 offering similar recognition faces; specifically Leu62(i), Ile65 (i+3), Phe69 (i+7) in the Bim-BH3 α-helix and Phe19 (i), Trp23 (i+4), and Leu26 (i+7) in the α-helix of the p53 transactivation domain (TAD). Although multiple clinical trials are on-going with new Mcl-1 and HDM2 inhibitors, a prevalent theme amongst the failures of newer cancer drugs is the development of resistance, and so multi-target drugs may be more clinically viable. We hypothesize that a single, dual inhibitor that functions to mimic both the Bim-BH3 and p53TAD helical recognition faces will simultaneously target both Mcl-1 and HDM2, affording a particularly efficacious drug through anticipated synergistic effects. Recently, triply-substituted indoles have elicited significant and selective inhibition of Mcl-1 and, in independent research, of HDM2. Therefore, we are leveraging these findings towards the discovery of dual Mcl-1/HDM2 inhibitors based on densely-functionalized indole cores, and our progress will be reported.

Polypharmacology approach to design dual inhibitors against oncoproteins Mcl-1 and HDM2 with densely functionalized indole scaffolds

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.