BSJ-4-116

• CAT Number: I044455
• CAS Number: 2519823-34-6
• Molecular Formula: C40H49ClN8O8S
• Molecular Weight: 837.38
• Purity: ≥95%
• Synonyms: N-[7-[(3R)-3-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]piperidin-1-yl]heptyl]-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide
• InChI: InChI=1S/C40H49ClN8O8S/c1-25(2)58(55,56)32-16-7-6-14-29(32)45-36-28(41)22-43-40(47-36)44-26-12-11-21-48(23-26)20-9-5-3-4-8-19-42-34(51)24-57-31-15-10-13-27-35(31)39(54)49(38(27)53)30-17-18-33(50)46-37(30)52/h6-7,10,13-16,22,25-26,30H,3-5,8-9,11-12,17-21,23-24H2,1-2H3,(H,42,51)(H,46,50,52)(H2,43,44,45,47)/t26-,30?/m1/s1
• InChIKey: YJOJMGTVKMABKQ-FIQOPJFZSA-N
• SMILES: CC(C)S(=O)(=O)C1=CC=CC=C1NC2=NC(=NC=C2Cl)NC3CCCN(C3)CCCCCCCNC(=O)COC4=CC=CC5=C4C(=O)N(C5=O)C6CCC(=O)NC6=O

BSJ-4-116 is a PROTAC connected by ligands for Cereblon and CDK. BSJ-4-116 is a highly potent and selective CDK12 degrader (PROTAC) with an IC50 of 6 nM. BSJ-4-116 downregulates DDR genes through a premature termination of transcription, primarily through increasing poly(adenylation). BSJ-4-116 exhibits potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor Olaparib (HY-10162)[1].
BSJ-4-116 (10-10000 nM; 72 hours) exhibits potent antiproliferative effects in Kelly CDK12C1039F[1].
BSJ-4-116 (50 nM; 6-24 hours) decreases the level of CDK12 protein, regardless of the mutational status of the cell line[1].
BSJ-4-116 inhibits the growth of T-ALL cells (Jurkat and MOLT-4 cells) and sensitizes them to PARP inhibition[1].
BSJ-4-116 regulates DDR genes via poly(adenylation). BSJ-4-116 overcomes CDK12C1039F mutation. BSJ-4-116 represents the first example of resistance to a bivalent degrader molecule that is a consequence of an acquired point mutation in the target protein[1].

Reference

[1]. Jiang B, et al. Discovery and resistance mechanism of a selective CDK12 degrader. Nat Chem Biol. 2021;17(6):675-683.
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