Structure of sevabertinib, an enzymatic, reversible inhibitor of EGFR/ERBB2.
United States Patent, Siegel et al., 2022.
United States Patent, Siegel et al., 2022.
Genome-inspired Cancer Drug Discovery
Cancer is a disease of the genome. Cancer cells carry different genomic alterations compared to normal cells, many of which are prime targets for effective anti-cancer therapies. Currently there is no therapeutic approach for many of the most common genome alterations—among them alterations in MYC, p53 and telomerase. Much of our work in the Meyerson lab is focused on advancing efforts to develop and improve new and existing cancer therapies.
Our work on telomerase has led to a clear analysis of the indications for telomerase inhibition in the treatment of glioblastoma based on cell line and xenograft dependency (Aquilanti et al., 2023), as well as a potential framework for further discovery of small molecule inhibitors of telomerase (Aquilanti et al., 2025). Further efforts have yielded a screening method for potential inhibitors of telomerase which has identified 2 compounds with a direct inhibitory effect on telomerase. Furthermore, our work with SLFN12 and PDE3A in glioblastoma has also led to the discovery that velcrin molecules can selectively kill glioblastoma cells with high SLFN12 and PDE3A expression levels (Aquilanti et al., 2024).
Recent collaborative efforts on p53 have led to an approach capable of inducing cell death in p53 mutant cells via small molecules, a promising and novel avenue for the treatment of all p53 mutant cancers (Sadagopan et al., 2024). The approach uses the increased concentration of p53 protein in these mutant cells, enabling small molecules to bind to a specific protein change and pool PLK1 inhibitors to induce selective cell death. This method potentially provides an avenue for robustly targeting p53 abundance in cancer cells, opening new doors for drugging the most commonly mutated gene in cancer.
As part of our efforts to advance the treatment of non small-cell lung cancer, in collaboration with Bayer, we have successfully worked to develop a novel targeted therapy, sevabertinib, for the treatment of NSCLC with somatic ERBB2 mutations. Phase 1/2 clinical trials have yielded an overall response rate of 59% and a disease control rate of 84%, along with similar response rates between pre-treated and first-line patients. Based on these results, the FDA has decided to grant sevabertinib priority review for application as a new drug as it continues through a phase 3 SOHO-02 trial. Stay tuned for more updates!
Our work on telomerase has led to a clear analysis of the indications for telomerase inhibition in the treatment of glioblastoma based on cell line and xenograft dependency (Aquilanti et al., 2023), as well as a potential framework for further discovery of small molecule inhibitors of telomerase (Aquilanti et al., 2025). Further efforts have yielded a screening method for potential inhibitors of telomerase which has identified 2 compounds with a direct inhibitory effect on telomerase. Furthermore, our work with SLFN12 and PDE3A in glioblastoma has also led to the discovery that velcrin molecules can selectively kill glioblastoma cells with high SLFN12 and PDE3A expression levels (Aquilanti et al., 2024).
Recent collaborative efforts on p53 have led to an approach capable of inducing cell death in p53 mutant cells via small molecules, a promising and novel avenue for the treatment of all p53 mutant cancers (Sadagopan et al., 2024). The approach uses the increased concentration of p53 protein in these mutant cells, enabling small molecules to bind to a specific protein change and pool PLK1 inhibitors to induce selective cell death. This method potentially provides an avenue for robustly targeting p53 abundance in cancer cells, opening new doors for drugging the most commonly mutated gene in cancer.
As part of our efforts to advance the treatment of non small-cell lung cancer, in collaboration with Bayer, we have successfully worked to develop a novel targeted therapy, sevabertinib, for the treatment of NSCLC with somatic ERBB2 mutations. Phase 1/2 clinical trials have yielded an overall response rate of 59% and a disease control rate of 84%, along with similar response rates between pre-treated and first-line patients. Based on these results, the FDA has decided to grant sevabertinib priority review for application as a new drug as it continues through a phase 3 SOHO-02 trial. Stay tuned for more updates!
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Safety and anti-tumor activity of BAY 2927088 in patients with HER2-mutant NSCLC: Results from an expansion cohort of the SOHO-01 phase I/II study.Nicolas Girard, Tae Min Kim, Hye Ryun Kim, Herbert H. Loong, Yuki Shinno, Shun Lu, Yong Fang, Jun Zhao, Kazumi Nishino, Ki Hyeong Lee, Liyun Miao, Tomohiro Sakamoto, Enriqueta Felip, Tsung-Ying Yang, Christophe Alfons Dooms, Daniel Shao-Weng Tan, Xiuning Le, Jan Christoph Brase, Paolo Grassi, and Koichi Goto
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Sevabertinib PatentStephan Siegel, Franziska Siegel, Volker Schulze, Markus Berger, Keith Graham, Ulrich Klar, Knut Eis, Detlev Sülzle, Ulf Bömer, Daniel Korr, Kirstin Petersen, Ursula Mönning, Uwe Eberspächer, Dieter Moosmayer, Matthew Meverson, Heidi Greulich, Bethany Kaplan, Hassan Youssef Harb, Phi Manh Dinh
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Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomicsLuc de Waal, Timothy A Lewis, Matthew G Rees, Aviad Tsherniak, Xiaoyun Wu, Peter S Choi, Lara Gechijian, Christina Hartigan, Patrick W Faloon, Mark J Hickey, Nicola Tolliday, Steven A Carr, Paul A Clemons, Benito Munoz, Bridget K Wagner, Alykhan F Shamji, Angela N Koehler, Monica Schenone, Alex B Burgin, Stuart L Schreiber, Heidi Greulich, Matthew Meyerson
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Safety and anti-tumor activity of BAY 2927088 in patients with HER2-mutant NSCLC: Results from an expansion cohort of the SOHO-01 phase I/II study.
Nicolas Girard, Tae Min Kim, Hye Ryun Kim, Herbert H. Loong, Yuki Shinno, Shun Lu, Yong Fang, Jun Zhao, Kazumi Nishino, Ki Hyeong Lee, Liyun Miao, Tomohiro Sakamoto, Enriqueta Felip, Tsung-Ying Yang, Christophe Alfons Dooms, Daniel Shao-Weng Tan, Xiuning Le, Jan Christoph Brase, Paolo Grassi, and Koichi Goto
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Velcrin molecular glues induce apoptosis in glioblastomas with high PDE3A and SLFN12 expression
Elisa Aquilanti, Silvia Goldoni, Andrew Baker, Kristyna Kotynkova, Sawyer Andersen, Vincent Bozinov, Galen F Gao, Andrew D Cherniack, Martin Lange, Ralf Lesche, Charlotte Kopitz, Philip Lienau, Timothy A Lewis, Marine Garrido, Stefan Gradl, Henrik Seidel, Yuen-Yi Tseng, Keith L Ligon, Patrick Y Wen, Matthew Meyerson, Heidi Greulich
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Bifunctional Small Molecules That Induce Nuclear Localization and Targeted Transcriptional Regulation
William J. Gibson, Ananthan Sadagopan, Veronika M. Shoba, Amit Choudhary, Matthew Meyerson, Stuart L. Schreiber
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