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 exhibite...
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| Format: | Article |
| Language: | English |
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The Royal Society
2024-12-01
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| Series: | Open Biology |
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| Online Access: | https://royalsocietypublishing.org/doi/10.1098/rsob.240210 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Anuradha F. Lingappa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c6fa5e29cb2b428cb59f6f90aa2ecaeb |
| institution | OA Journals |
| issn | 2046-2441 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj-art-c6fa5e29cb2b428cb59f6f90aa2ecaeb2025-08-20T01:58:12ZengThe Royal SocietyOpen Biology2046-24412024-12-01141210.1098/rsob.240210Small molecule protein assembly modulators with pan-cancer therapeutic efficacyAnuradha F. Lingappa0Olayemi Akintunde1Erin Samueli2Connie Ewald3Maya Michon4Niloufar Ziari5Ming Lu6Shao Feng Yu7Markus Froehlich8Phuong Uyen Le9Yuniel Fernandez10Suguna Mallesh11Jim Lin12Anatoliy Kitaygorodskyy13Dennis Solas14Jonathan C. Reed15Jaisri R. Lingappa16Andreas Müller-Schiffmann17Carsten Korth18Dharma Prasad19Aysegul Nalca20Emily Aston21Brad Fabbri22Sanjeev K. Anand23Thomas W. Campi24Emma Petrouski25Debendranath Dey26David W. Andrews27James L. Rubenstein28Vishwanath R. Lingappa29Prosetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAUniversity of California San Francisco, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USASunnybrook Research Institute, Toronto, ON, CanadaSunnybrook Research Institute, Toronto, ON, CanadaProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USADepartment of Global Health, University of Washington, Seattle, WA, USADepartment of Global Health, University of Washington, Seattle, WA, USAInstitute of Neuropathology, Heinrich Heine University, Dusseldorf, GermanyInstitute of Neuropathology, Heinrich Heine University, Dusseldorf, GermanyProsetta Biosciences, San Francisco, CA, USAUnited States Army Medical Research Institute for Infectious Diseases, Frederick, MD, USATechAccel, Overland Park, KS, USATechAccel, Overland Park, KS, USAModulant Biosciences, Fishers, IN, USAModulant Biosciences, Fishers, IN, USAProsetta Biosciences, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USASunnybrook Research Institute, Toronto, ON, CanadaUniversity of California San Francisco, San Francisco, CA, USAProsetta Biosciences, San Francisco, CA, USATwo 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.https://royalsocietypublishing.org/doi/10.1098/rsob.240210drug discoverypan-cancer therapeuticsallosteric modulatorrestoration of homeostasismulti-protein complex |
| spellingShingle | 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 Small molecule protein assembly modulators with pan-cancer therapeutic efficacy Open Biology drug discovery pan-cancer therapeutics allosteric modulator restoration of homeostasis multi-protein complex |
| title | Small molecule protein assembly modulators with pan-cancer therapeutic efficacy |
| title_full | Small molecule protein assembly modulators with pan-cancer therapeutic efficacy |
| title_fullStr | Small molecule protein assembly modulators with pan-cancer therapeutic efficacy |
| title_full_unstemmed | Small molecule protein assembly modulators with pan-cancer therapeutic efficacy |
| title_short | Small molecule protein assembly modulators with pan-cancer therapeutic efficacy |
| title_sort | small molecule protein assembly modulators with pan cancer therapeutic efficacy |
| topic | drug discovery pan-cancer therapeutics allosteric modulator restoration of homeostasis multi-protein complex |
| url | https://royalsocietypublishing.org/doi/10.1098/rsob.240210 |
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