DT2216

DT2216 is a proteolysis-targeting chimera (PROTAC) composed of the Bcl-2 family inhibitor ABT-263 (Cay-11500) conjugated to a von Hippel-Lindau (VHL) E3 ligase ligand. It selectively induces degradation of Bcl-xL in MOLT-4 T cell acute lymphoblastic leukemia (T-ALL) cells with a 50% degradation concentration (DC50) value of 63 nM and maximum degradation (Dmax) of 90.8% over washed isolated human platelets with a Dmax of 26% at 3 µM. DT2216 selectively binds to Bcl-xL and Bcl-2 over Bcl-W (Kis = 12.82, 1.82, and 300.9 nM, respectively) but does not induce degradation of Bcl-2 or Bcl-W in RS4,11 B-ALL cells at 1 µM. It is cytotoxic to MOLT-4 cells but not washed isolated human platelets (EC50s = 0.052 and >3 µM, respectively) and induces cleavage of caspase-3 in MOLT-4 cells when used at concentrations of 100 and 300 nM. DT2216 (15 mg/kg) reduces tumor volume and weight in a MOLT-4 mouse xenograft model. It acts synergistically with the Bcl-2 inhibitor ABT-199 (Cay-16233) in an NCI H146 small cell lung cancer (SCLC) mouse xenograft model and the microtubule-stabilizing anticancer agent docetaxel (Cay-11637) in an MDA-MB-231 breast cancer mouse xenograft model.Formal Name: (2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. CAS Number: 2365172-42-3. Molecular Formula: C77H96ClF3N10O10S4. Formula Weight: 1542.4. Purity: >98%. Formulation: (Request formulation change), A solid. Solubility: DMF: 25 mg/ml, DMSO: 20 mg/ml, Ethanol: 25 mg/ml. lambdamax: 275, 315 nm. SMILES: CC(C)(C1)CCC(C2=CC=C(C=C2)Cl)=C1CN3CCN(C4=CC=C(C=C4)C(NS(=O)(C5=CC(S(C(F)(F)F)(=O)=O)=C(C=C5)N[C@@H](CSC6=CC=CC=C6)CCN7CCN(CC7)C(CCCCCC(N[C@@H](C(C)(C)C)C(N8[C@@H](C[C@H](C8)O)C(N[C@H](C9=CC=C(C%10=C(N=CS%10)C)C=C9)C)=O)=O)=O)=O)=O)=O)CC3. InChi Code: InChI=1S/C77H96ClF3N10O10S4/c1-51(53-18-20-55(21-19-53)70-52(2)82-50-103-70)83-73(96)66-44-61(92)48-91(66)74(97)71(75(3,4)5)85-68(93)16-12-9-13-17-69(94)90-42-36-87(37-43-90)35-33-59(49-102-62-14-10-8-11-15-62)84-65-31-30-63(45-67(65)104(98,99)77(79,80)81)105(100,101)86-72(95)56-24-28-60(29-25-56)89-40-38-88(39-41-89)47-57-46-76(6,7)34-32-64(57)54-22-26-58(78)27-23-54/h8,10-11,14-15,18-31,45,50-51,59,61,66,71,84,92H,9,12-13,16-17,32-44,46-49H2,1-7H3,(H,83,96)(H,85,93)(H,86,95)/t51-,59+,61+,66-,71+/m0/s1. InChi Key: PXVFFBGSTYQHRO-REQIQPEASA-N.