生物活性

• 描述BCL-2 is the founding member of the BCL-2 family of apoptosis regulatory proteins that either induce (pro-apoptotic) or inhibit (anti-apoptotic) apoptosis. The anti-apoptotic BCL-2 is classified as an oncogene, as damage to the BCL-2 gene has been shown to cause a number of cancers, including lymphoma^[1]. Myeloid cell leukemia-1 (MCL-1), a member of antiapoptotic BCL-2 family proteins, is a key regulator of mitochondrial homeostasis. Frequent overexpression of MCL-1 in human primary and drug-resistant cancer cells makes it an attractive cancer therapeutic target^[2]. MIK665 is a special Mcl-1 inhibitor. It has an IC50 of 1.81 nM. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphere assays. The combination-induced cell death was independent of BIM, and NOXA. Recapitulated in mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity and had tolerable toxicity^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03672695	Acute Myeloid Leukaemia	Phase 1	Not yet recruiting	March 31, 2022	United States, Connecticut ... more >> Smilow Cancer Hospital at Yale Not yet recruiting New Haven, Connecticut, United States, 06511 United States, Texas The University of Texas MD Anderson Cancer Center, Houston, TX Not yet recruiting Houston, Texas, United States, 77030 Australia Peter MacCallum cancer centrer Not yet recruiting Melbourne, Australia The Alfred Hospital Department of Haematology Not yet recruiting Victoria Park, Australia France Institut Paoli-Calmettes Not yet recruiting Marseille, France Hopital Saint-Antoine Not yet recruiting Paris, France Institut Universitaire du Cancer Toulouse - Oncopole Not yet recruiting Toulouse, France Collapse <<
  NCT02979366	Acute Myeloid Leukaemia (AML) ... more >> Myelodysplastic Syndrome (MDS) Collapse <<	Phase 1	Recruiting	October 2020	United States, Connecticut ... more >> Patient Care Location: Smilow Cancer Hospital at Yale Recruiting New Haven, Connecticut, United States, 06511 United States, Texas The University of Texas MD Anderson Cancer Center, Department of Leukemia, Division of Cancer Medicine Recruiting Houston, Texas, United States, 77030 Australia The Alfred Hospital Department of Haematology Recruiting Melbourne, Australia, 3004 Royal Melbourne Hospital, Department of Clinical Haematology and BMT Service Recruiting Melbourne, Australia, 3050 France Institut Paoli-Calmettes Departement d'Hématologie Recruiting Marseille, France, 13009 Hôpital Saint-Antoine Département d'Hematologie Clinique et de Thérapie cellulaire Recruiting Paris, France, 75012 Spain Hospital Universitario Vall d' Hebron/VHIO Hematology Department Recruiting Barcelona, Spain, 08035 Hospital Universitario La Fe Hematology Department Recruiting Valencia, Spain, 46026 Collapse <<
  NCT02992483	Multiple Myeloma (MM), Lymphom... more >>a, Large B-Cell, Diffuse (DLBCL), Lymphoma Collapse <<	Phase 1	Recruiting	April 15, 2020	United States, Ohio ... more >> Novartis Investigative Site Recruiting Columbus, Ohio, United States, 43210 United States, Texas Novartis Investigative Site Recruiting Houston, Texas, United States, 77030 Australia, Victoria Novartis Investigative Site Recruiting Heidelberg, Victoria, Australia, 3084 France Novartis Investigative Site Recruiting Nantes Cedex 1, France, 44093 Germany Novartis Investigative Site Recruiting Heidelberg, Germany, 69120 Novartis Investigative Site Recruiting Kiel, Germany, 24105 Italy Novartis Investigative Site Recruiting Rozzano, MI, Italy, 20089 Japan Novartis Investigative Site Recruiting Fukuoka-city, Fukuoka, Japan, 811-1395 Spain Novartis Investigative Site Recruiting Salamanca, Castilla Y Leon, Spain, 37007 Collapse <<

• 参考文献

• [1] Abdul Shukkur Ebrahim,et al. Hematologic malignancies: newer strategies to counter the BCL-2 protein. J Cancer Res Clin Oncol. 2016. 142(9), 2013-22.

  [2] Weiguo Xiang,et al. MCL-1 inhibition in cancer treatment. Onco Targets Ther. 2018. 11, 7301-7314.

  [3] Nabanita Mukherjee,et al. MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells. Cell Death Dis. 2020. 11(6), 443.