I-BET762

I-BET762 (GSK-525762A, Molibresib) is a highly potent, selective inhibitor of BET family proteins BRD2, BRD3 and BRD4 with IC50 of 32.5-42.5 nM, does not interact with other bromodomain-containing proteins (BAZ2B, ATAD2, CREBBP and PCAF) ; inhibits binding of BET proteins to acetylated histones, disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, suppresses TNF-inducible key proinflammatory cytokine (il1b, il1a) and chemokine genes (ccl5, cxcl10, cxcl2/3) in BMDMs; inhibits the ability of Th1-differentiated 2D2 T cells to induce neuroinflammation in vivo in mouse model of EAE; inhibits myeloma cell proliferation both in vitro and myeloma xenograft models.Blood Cancer Phase 2 Clinical (In Vitro) :Molibresib (I-BET 762) shows the highest affinity interaction with BET. Molibresib binds to the tandem bromodomains of BET with high affinity (dissociation constant Kd of 50.5-61.3 nM) . Molibresib displaces, with high efficacy (half-maximum inhibitory concentration IC50 of 32.5-42.5 nM), a tetra-acetylated H4 peptide that had been pre-bound to tandem bromodomains of BET. Molibresib has high affinity for BD1/BD2 domain of BRD2/3/4 proteins. Molibresib treatment leads to a reduction in the recruitment of all three proteins to chromatin. Molibresib inhibits OPM-2 cell proliferation with IC50 of 60.15 nM. (In Vivo) :The antimyeloma activity of Molibresib (I-BET 762) is tested dosed orally in an in vivo systemic xenograft model generated by injecting OPM-2 cells into NOD-SCID mice. Daily oral doses of Molibresib up to 10 mg/kg and 30 mg/kg given every other day are well tolerated with no clear impact on body weight compared with vehicle control. The plasma hLC concentration is significantly reduced in mice treated with Molibresib.