I-BET762

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

I-BET762（GSK-525762A，Molibresib）是一种高效、选择性的 BET 家族蛋白抑制剂。

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.

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.

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.

GSK525762A | GSK-525762A | I-BET-762 | Molibresib

Chromatin/Epigenetic

Bromodomain

BETproteins

Cancer

Blood cancer

1260907-17-2

423.8954

C22H22ClN5O2

>98% (HPLC)

10 mM in DMSO

O=C(NCC)C[C@H]1C2=NN=C(C)N2C3=CC=C(OC)C=C3C(C4=CC=C(Cl)C=C4)=N1

4H-[1,2,4]Triazolo[4,3-a][1,4]benzodiazepine-4-acetamide, 6-(4-chlorophenyl)-N-ethyl-8-methoxy-1-methyl-, (4S)-

(-20℃)

With Ice Pack

≥ 2 years