6paf

From Proteopedia

Co-crystal Structure of human SMYD3 with Isoxazole Amides Inhibitors

Structural highlights

6paf is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.241Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SMYD3_HUMAN Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.^[1] ^[2]

Publication Abstract from PubMed

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described. The synthesis and biological and pharmacokinetic profiles of compounds are also presented.

Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.,Su DS, Qu J, Schulz M, Blackledge CW, Yu H, Zeng J, Burgess J, Reif A, Stern M, Nagarajan R, Pappalardi MB, Wong K, Graves AP, Bonnette W, Wang L, Elkins P, Knapp-Reed B, Carson JD, McHugh C, Mohammad H, Kruger R, Luengo J, Heerding DA, Creasy CL ACS Med Chem Lett. 2019 Dec 27;11(2):133-140. doi:, 10.1021/acsmedchemlett.9b00493. eCollection 2020 Feb 13. PMID:32071679^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol. 2004 Aug;6(8):731-40. Epub 2004 Jul 4. PMID:15235609 doi:10.1038/ncb1151
↑ Van Aller GS, Reynoird N, Barbash O, Huddleston M, Liu S, Zmoos AF, McDevitt P, Sinnamon R, Le B, Mas G, Annan R, Sage J, Garcia BA, Tummino PJ, Gozani O, Kruger RG. Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics. 2012 Apr;7(4):340-3. doi: 10.4161/epi.19506. Epub 2012 Apr 1. PMID:22419068 doi:10.4161/epi.19506
↑ Su DS, Qu J, Schulz M, Blackledge CW, Yu H, Zeng J, Burgess J, Reif A, Stern M, Nagarajan R, Pappalardi MB, Wong K, Graves AP, Bonnette W, Wang L, Elkins P, Knapp-Reed B, Carson JD, McHugh C, Mohammad H, Kruger R, Luengo J, Heerding DA, Creasy CL. Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors. ACS Med Chem Lett. 2019 Dec 27;11(2):133-140. doi:, 10.1021/acsmedchemlett.9b00493. eCollection 2020 Feb 13. PMID:32071679 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00493