ZXH-3-26

• CAT Number: I019307
• CAS Number: 2243076-67-5
• Molecular Formula: C38H37ClN8O7S
• Molecular Weight: 785.27
• Purity: ≥95%
• Synonyms: methyl 2-[(9S)-7-(4-chlorophenyl)-4-[5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentylcarbamoyl]-5,13-dimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate
• InChI: InChI=1S/C38H37ClN8O7S/c1-19-29-31(21-10-12-22(39)13-11-21)42-25(18-28(49)54-3)33-45-44-20(2)46(33)38(29)55-32(19)35(51)41-17-6-4-5-16-40-24-9-7-8-23-30(24)37(53)47(36(23)52)26-14-15-27(48)43-34(26)50/h7-13,25-26,40H,4-6,14-18H2,1-3H3,(H,41,51)(H,43,48,50)/t25-,26?/m0/s1
• InChIKey: OTKOFICOCDRNDA-PMCHYTPCSA-N
• SMILES: CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)OC)C4=CC=C(C=C4)Cl)C(=O)NCCCCCNC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O

ZXH-3-26 is a PROTAC connected by ligands for Cereblon and BRD4 with a DC50/5h of 5 nM. The DC50/5h refers to half-maximal degradation after 5 hours of treatment of ~ 5 nM[1].
ZXH-3-26 represents the first small molecule to allow pharmacologic targeting of BRD4 without significant inhibition or degradation of BRD2/3[1].
ZXH-3-26 shows activity exclusively on the first bromodomain of BRD4, and spares degradation of BRD2/3 at concentrations 10 μM. Immunoblot analysis confirms that ZXH-3-26 degrades endogenous BRD4 with comparable efficacy compared to the best pan-BET degrader dBET6, while being inactive on BRD2/3[1].
ZXH-3-26 engages CRBN in a conformation distinct[1].

Reference

[1]. Nowak RP, et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat Chem Biol. 2018 Jul;14(7):706-714.
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