Open Biology (Dec 2024)
Small molecule protein assembly modulators with pan-cancer therapeutic efficacy
- Anuradha F. Lingappa,
- Olayemi Akintunde,
- Erin Samueli,
- Connie Ewald,
- Maya Michon,
- Niloufar Ziari,
- Ming Lu,
- Shao Feng Yu,
- Markus Froehlich,
- Phuong Uyen Le,
- Yuniel Fernandez,
- Suguna Mallesh,
- Jim Lin,
- Anatoliy Kitaygorodskyy,
- Dennis Solas,
- Jonathan C. Reed,
- Jaisri R. Lingappa,
- Andreas Müller-Schiffmann,
- Carsten Korth,
- Dharma Prasad,
- Aysegul Nalca,
- Emily Aston,
- Brad Fabbri,
- Sanjeev K. Anand,
- Thomas W. Campi,
- Emma Petrouski,
- Debendranath Dey,
- David W. Andrews,
- James L. Rubenstein,
- Vishwanath R. Lingappa
Affiliations
- Anuradha F. Lingappa
- Prosetta Biosciences, San Francisco, CA, USA
- Olayemi Akintunde
- Prosetta Biosciences, San Francisco, CA, USA
- Erin Samueli
- Prosetta Biosciences, San Francisco, CA, USA
- Connie Ewald
- Prosetta Biosciences, San Francisco, CA, USA
- Maya Michon
- Prosetta Biosciences, San Francisco, CA, USA
- Niloufar Ziari
- Prosetta Biosciences, San Francisco, CA, USA
- Ming Lu
- University of California San Francisco, San Francisco, CA, USA
- Shao Feng Yu
- Prosetta Biosciences, San Francisco, CA, USA
- Markus Froehlich
- Prosetta Biosciences, San Francisco, CA, USA
- Phuong Uyen Le
- Sunnybrook Research Institute, Toronto, ON, Canada
- Yuniel Fernandez
- Sunnybrook Research Institute, Toronto, ON, Canada
- Suguna Mallesh
- Prosetta Biosciences, San Francisco, CA, USA
- Jim Lin
- Prosetta Biosciences, San Francisco, CA, USA
- Anatoliy Kitaygorodskyy
- Prosetta Biosciences, San Francisco, CA, USA
- Dennis Solas
- Prosetta Biosciences, San Francisco, CA, USA
- Jonathan C. Reed
- Department of Global Health, University of Washington, Seattle, WA, USA
- Jaisri R. Lingappa
- Department of Global Health, University of Washington, Seattle, WA, USA
- Andreas Müller-Schiffmann
- Institute of Neuropathology, Heinrich Heine University, Dusseldorf, Germany
- Carsten Korth
- Institute of Neuropathology, Heinrich Heine University, Dusseldorf, Germany
- Dharma Prasad
- Prosetta Biosciences, San Francisco, CA, USA
- Aysegul Nalca
- United States Army Medical Research Institute for Infectious Diseases, Frederick, MD, USA
- Emily Aston
- TechAccel, Overland Park, KS, USA
- Brad Fabbri
- TechAccel, Overland Park, KS, USA
- Sanjeev K. Anand
- Modulant Biosciences, Fishers, IN, USA
- Thomas W. Campi
- Modulant Biosciences, Fishers, IN, USA
- Emma Petrouski
- Prosetta Biosciences, San Francisco, CA, USA
- Debendranath Dey
- Prosetta Biosciences, San Francisco, CA, USA
- David W. Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- James L. Rubenstein
- University of California San Francisco, San Francisco, CA, USA
- Vishwanath R. Lingappa
- Prosetta Biosciences, San Francisco, CA, USA
- DOI
- https://doi.org/10.1098/rsob.240210
- Journal volume & issue
-
Vol. 14,
no. 12
Abstract
Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations. Anti-tumour properties of both chemotypes were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex. Treatment with these compounds alters the target multi-protein complexes in a manner that appears to remove a block, crucial for cancer survival and progression, on a homeostatic linkage between uncontrolled proliferation and apoptosis. These compounds provide starting points for development of novel, next-generation, non-toxic, pan-cancer therapeutics.
Keywords
- drug discovery
- pan-cancer therapeutics
- allosteric modulator
- restoration of homeostasis
- multi-protein complex
