S63845 is an effective and selective inhibitor of bone marrow cell leukemia 1 (MCL1), with a Kd value of 0.19nM (for human MCL1) [1]. MCL1 is a pro-survival protein belonging to the BCL-2 family and is overexpressed in many cancers [2]. S63845 can be used for therapeutic research on multiple myeloma, leukemia, and lymphoma cell lines [3].
In vitro, S63845 (0.25, 0.5, and 1.0μM; 24 and 48h) significantly induces apoptosis in two cell lines (HH and HuT-78) in a dose-dependent manner, with decreased cell viability, loss of mitochondrial membrane potential, and activation of caspases [4]. S63845 (0-1280nM; 32 and 48h) in combination with the tyrosine kinase inhibitor imatinib reduces the viability of two cells (K562 and JURL-MK1), and significantly reduces the expression of MCL1, cIAP1, and survivin in K562 cells, while there is a slight upregulation in TCCS cells [5].
In vivo, S63845 (25 and 50mg/kg/day for 5 days; intravenous) can inhibit the generation of red blood cells (RBC) and lymph (LYMPH) in the blood of mice with hematopoietic injury models in the early stage, and restore it in the late stage. During the entire observation period, the platelet (PLT) count in the blood increases [6]. S63845 (25mg/kg/day; twice per week for 3 weeks; intravenous) in combination with regorafenib significantly improves the survival rate of mice in the 143B-luc lung metastasis model [7].
References:
[1] Kotschy A, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 27;538(7626):477-482.
[2] Li Z, He S, Look A T. The MCL1-specific inhibitor S63845 acts synergistically with venetoclax/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells[J]. Leukemia, 2019, 33(1): 262-266.
[3] Algarín E M, Díaz-Tejedor A, Mogollón P, et al. Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma[J]. Haematologica, 2020, 105(3): e116.
[4] Sumarni U, Zhu J, Sinnberg T, et al. Sensitivity of cutaneous T-cell lymphoma cells to the Mcl-1 inhibitor S63845 correlates with the lack of Bcl-w expression[J]. International Journal of Molecular Sciences, 2022, 23(20): 12471.
[5] Malyukova A, Ujvari D, Yektaei-Karin E, et al. Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells[J]. Cell Death & Disease, 2021, 12(10): 875.
[6] Zhang H, Li F, Yang M, et al. MCL-1 Inhibitor S63845 Distinctively Affects Intramedullary and Extramedullary Hematopoiesis[J]. Pharmaceutics, 2023, 15(4): 1085.
[7] Ji Y, Harris M A, Newton L M, et al. Osteosarcoma cells depend on MCL-1 for survival, and osteosarcoma metastases respond to MCL-1 antagonism plus regorafenib in vivo[J]. BMC cancer, 2024, 24(1): 1350.
S63845是一种有效的选择性骨髓细胞白血病1（MCL1）抑制剂，Kd值为0.19nM（人MCL1） [1]。MCL1是一种属于BCL-2家族蛋白的促存活蛋白，在许多癌症中过度表达 [2]。S63845可用于多发性骨髓瘤、白血病和淋巴瘤细胞系的治疗研究 [3]。
在体外，S63845（0.25, 0.5 and 1.0μM; 24, 48h）以剂量依赖的方式显著诱导两种细胞系（HH、HuT-78）发生凋亡，细胞活力下降，线粒体膜电位丧失和半胱天冬酶激活 [4]。S63845（0-1280nM; 32, 48h）与酪氨酸激酶抑制剂imatinib的联合治疗降低了两种细胞（K562和JURL-MK1）的活力，并且显著降低了K562细胞中MCL1、cIAP1和survivin的表达，而在TCCS细胞中则有轻微上调作用 [5]。
在体内，S63845（25 and 50mg/kg/day for 5 days; i.v.）在早期能够抑制造血损伤模型小鼠血液中红细胞（RBC）和淋巴（LYMPH）的生成，而在晚期恢复。在整个观察期间血液中血小板（PLT）计数增加 [6]。S63845（25mg/kg/day; twice per week for 3 weeks; i.v.）与regorafenib联合治疗显著提高了143B-luc肺转移瘤模型小鼠的生存率 [7]。