Frontiers of Science: Allosteric activators of protein phosphatase 2A display broad antitumor activity
Prof. Thomas Look, Harvard Medical School and Dana-Farber Cancer Institute, Boston, US
Allosteric activators of protein phosphatase 2A display broad antitumor activity
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Students and early-career postdocs are welcome to share a virtual cup of coffee and discuss with Prof. Look after the seminar. This is a great possibility to learn hosting skills in friendly environment and create connections for future. Every student are welcome to join, in spite of which research group they belong to.
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Thomas Look, M.D., is a Professor of Pediatrics at Harvard Medical School and a member of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute, as well as a co-Leader of the Dana-Farber/Harvard Cancer Center’s Leukemia Program. Over the past four decades, Look has published 348 peer-reviewed papers addressing the molecular basis of malignant transformation, aberrant proliferation and apoptosis in cancer cells and the application of molecular genetic findings to improve the treatment of malignancies of children and adults, particularly T-cell acute leukemia, neuroblastoma and myelodysplastic syndrome.
Look has conducted genetic studies aimed at the identification of novel targets for cancer therapy, and he is now internationally recognized as a leader in this field. His laboratory has developed the first zebrafish transgenic models of T-cell acute lymphoblastic leukemia and childhood neuroblastoma, opening up the opportunity to apply the powerful genetic and chemical biology technology applicable to the zebrafish model to identify new molecular targets and small molecule drugs for therapy in these childhood cancers. His laboratory has also developed the first zebrafish models of myelodysplastic syndrome and clonal hematopoiesis due to loss of TET2, ASXL1 and DNMT3A, which he is using to identify drugs that selectively target mutant hematopoietic stem and progenitor cells, while sparing normal hematopoiesis. Recently, his group identified a class of small molecules called iHAPs, or improved heterocyclic activators of PP2A, that kill leukemia and solid tumor cells by allosterically assembling a specific heterotrimeric protein phosphatase 2A (PP2A) holoenzyme containing the B56ε regulatory subunit. These compounds stimulate PP2A-B56e phosphatase activity but do not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase, but is not toxic to normal dividing cell populations.
Morita K, He S, Nowak RP, Wang J, Zimmerman MW, Fu C, Durbin AD, Martel MW, Prutsch N, Gray NS, Fischer ES, Look AT. 2020. Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2. Cell. 181(3):702-715.e20
Tao T, Shi H, Mariani L, Abraham BJ, Durbin AD, Zimmerman MW, Powers JT, Missios P, Ross KN, Perez-Atayde AR, Bulyk ML, Young RA, Daley GQ, Look AT. 2020. LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors. Proc Natl Acad Sci U S A. 117(28):16516-16526
Jing CB, Fu C, Prutsch N, Wang M, He S, Look AT. 2020. Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells (HSPCs) with TOP1-targeted drugs and PARP1 inhibitors. Leukemia. 11; 34(11):2992-3006
Wang L, Tan TK, Durbin AD, Zimmerman MW, Abraham BJ, Tan SH, Ngoc PCT, Weichert-Leahey N, Akahane K, Lawton LN, Rokita JL, Maris JM, Young RA, Look AT, Sanda T. 2020. ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry. Nat Commun. 10(1):5622
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Mar 25, 2021 15:00