MS8815   Click here for help

GtoPdb Ligand ID: 12138

Synonyms: compound 16 [PMID: 35837138] | MS-8815
Compound class: Synthetic organic
Comment: MS8815 is a bifunctional PROTAC molecule that targets the enhancer of zeste homolog 2 (EZH2) protein for degradation [1]. It contains a VHL-binding ligand VHL-1 (a.k.a. VH032 [3]; PubChem CID 77232228; Kd 188 nM) to recruit the VHL E3 ligase, and the EZH2 engager is the FDA-approved drug tazemetostat (EPZ-6438). EZH2 overexpression is a marker of poor prognosis in triple-negative breast cancer (TNBC). Protein degrading agents are proposed as alternatives to small molecule inhibitors, and are of particular use for 'difficult-to-drug' protein targets.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 15
Hydrogen bond donors 5
Rotatable bonds 29
Topological polar surface area 237.85
Molecular weight 1153.64
XLogP 9.07
No. Lipinski's rules broken 3
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Canonical SMILES CCN(c1cc(cc(c1C)C(=O)NCc1c(C)cc([nH]c1=O)C)c1ccc(cc1)CN1CCN(CC1)C(=O)CCCCCCCC(=O)N[C@@H](C(C)(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)NCc1ccc(cc1)c1scnc1C)O)C1CCOCC1
Isomeric SMILES Cc1c(c(=O)[nH]c(c1)C)CNC(=O)c1cc(cc(c1C)N(C1CCOCC1)CC)c1ccc(cc1)CN1CCN(CC1)C(=O)CCCCCCCC(=O)N[C@H](C(=O)N1[C@@H](C[C@H](C1)O)C(=O)NCc1ccc(cc1)c1c(ncs1)C)C(C)(C)C
InChI InChI=1S/C65H87N9O8S/c1-9-73(51-25-31-82-32-26-51)55-35-50(34-53(44(55)4)61(78)67-38-54-42(2)33-43(3)69-62(54)79)48-21-19-47(20-22-48)39-71-27-29-72(30-28-71)58(77)16-14-12-10-11-13-15-57(76)70-60(65(6,7)8)64(81)74-40-52(75)36-56(74)63(80)66-37-46-17-23-49(24-18-46)59-45(5)68-41-83-59/h17-24,33-35,41,51-52,56,60,75H,9-16,25-32,36-40H2,1-8H3,(H,66,80)(H,67,78)(H,69,79)(H,70,76)/t52-,56+,60-/m1/s1
1. Dale B, Anderson C, Park KS, Kaniskan HÜ, Ma A, Shen Y, Zhang C, Xie L, Chen X, Yu X et al.. (2022)
Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2.
ACS Pharmacol Transl Sci, 5 (7): 491-507. [PMID:35837138]
2. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA et al.. (2013)
Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.
Proc Natl Acad Sci USA, 110 (19): 7922-7. [PMID:23620515]
3. Zengerle M, Chan KH, Ciulli A. (2015)
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4.
ACS Chem Biol, 10 (8): 1770-7. [PMID:26035625]