| Structural highlights
Function
MEP50_HUMAN Non-catalytic component of the 20S PRMT5-containing methyltransferase complex, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones. This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The 20S PRMT5-containing methyltransferase complex also methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage.[1] [2]
Publication Abstract from PubMed
Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.
Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.,Smith CR, Kulyk S, Ahmad MUD, Arkhipova V, Christensen JG, Gunn RJ, Ivetac A, Ketcham JM, Kuehler J, Lawson JD, Thomas NC, Wang X, Marx MA RSC Med Chem. 2022 Sep 27;13(12):1549-1564. doi: 10.1039/d2md00163b. eCollection , 2022 Dec 14. PMID:36545438[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G. A novel WD repeat protein component of the methylosome binds Sm proteins. J Biol Chem. 2002 Mar 8;277(10):8243-7. Epub 2001 Dec 26. PMID:11756452 doi:http://dx.doi.org/10.1074/jbc.M109984200
- ↑ Antonysamy S, Bonday Z, Campbell RM, Doyle B, Druzina Z, Gheyi T, Han B, Jungheim LN, Qian Y, Rauch C, Russell M, Sauder JM, Wasserman SR, Weichert K, Willard FS, Zhang A, Emtage S. Crystal structure of the human PRMT5:MEP50 complex. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17960-5. doi:, 10.1073/pnas.1209814109. Epub 2012 Oct 15. PMID:23071334 doi:http://dx.doi.org/10.1073/pnas.1209814109
- ↑ Smith CR, Kulyk S, Ahmad MUD, Arkhipova V, Christensen JG, Gunn RJ, Ivetac A, Ketcham JM, Kuehler J, Lawson JD, Thomas NC, Wang X, Marx MA. Fragment optimization and elaboration strategies series of PRMT5/MTA inhibitors from five fragment hits. RSC Med Chem. 2022 Sep 27;13(12):1549-1564. PMID:36545438 doi:10.1039/d2md00163b
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