Small molecule protein assembly modulators with pan-cancer therapeutic efficacy
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.
Authors
- Thomas W. Campi
- Anuradha F. Lingappa (ORCID: https://orcid.org/0009-0006-8976-4382)
- Olayemi Akintunde
- Dennis Solas
- Jaisri R. Lingappa (ORCID: https://orcid.org/0000-0002-7533-6276)
- Brad Fabbri
- Suguna Mallesh
- Vishwanath R. Lingappa (ORCID: https://orcid.org/0000-0003-0962-6571)
- Shao Feng Yu
- Niloufar Ziari
- Connie Ewald
- Sanjeev K. Anand (ORCID: https://orcid.org/0000-0001-7643-2019)
- Ayşegül Nalça (ORCID: https://orcid.org/0000-0001-8581-7535)
- Andreas Müller‐Schiffmann (ORCID: https://orcid.org/0000-0002-8079-4626)
- James L. Rubenstein (ORCID: https://orcid.org/0000-0002-9062-2449)
- David William Andrews (ORCID: https://orcid.org/0000-0002-9266-7157)
- Emma Petrouski
- Anatoliy Kitaygorodskyy
- Markus Froehlich
- Maya Michon (ORCID: https://orcid.org/0009-0005-7779-0666)
- Ming‐Chi Lu (ORCID: https://orcid.org/0000-0001-9051-0351)
- Carsten Korth (ORCID: https://orcid.org/0000-0003-1503-1822)
- Dharma Prasad
- Jonathan C. Reed (ORCID: https://orcid.org/0000-0003-4425-7636)
- Debendranath Dey (ORCID: https://orcid.org/0000-0002-9651-2080)
- Yessica Plata Fernández
- Phuong Uyen Le
- Jim Jung‐Ching Lin
- Emily Aston
- Erin Samueli
Institutions
- University of California, San Francisco (US)
- University of Washington (US)
- United States Army Medical Research Institute of Infectious Diseases (US)
- Sunnybrook Hospital (CA)
- Sunnybrook Research Institute
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Open Biology
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1098/rsob.240210
- Citations
- 5
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.75
Funders
- Leukemia and Lymphoma Society
- Leukemia and Lymphoma Society of Canada
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute