Role of AT-406 as a SMAC Mimetic in Cancer

Yıl 2018, Cilt: 4 Sayı: 2, 114 - 119, 01.01.2018

Berrin Tuğrul Merve İşseven

Öz

Endogenous SMACs are mitochondrial proapoptotic proteins that suppress the inhibitors of apoptosis proteins IAPs . Inhibitors of apoptosis proteins are highly expressed at many human cancers. Small molecule inhibitors of the inhibitors of apoptosis proteins mimicking the endogenous inhibitors of apoptosis proteins antagonist second mitochondria-derived activator of caspases are called SMAC mimetics. AT-406 that effectively targets XIAP and cIAP-1/2 is an orally active SMAC mimetic. It is stated that it highly efficiently inhibits the development of cancer cells in research related to various human cancer cell lines. It has been shown to induce apoptosis in xenograft tumor research in vivo in mice, rats, non-human primates and dogs. AT-406 has recently been investigated in phase I/II clinical trials for the treatment of human cancer. Our aim in this review was to present the research performed on AT-406 in various types of cancer cells

Anahtar Kelimeler

AT-406, SMAC mimetic, IAP proteins, Anticancer, Proapoptotic

SMAC Mimetiği Olarak AT-406?nın Kanserdeki Rolü

Öz

Endojen ikinci mitokondri kökenli kaspaz aktivatörleri SMAC , apoptozis inhibitör proteinleri IAPs ’ni baskılayan mitokondriyal pro-apoptotik proteinlerdir. Apoptozis inhibitör proteinleri bir çok insan kanserlerinde yüksek seviyede eksprese edilmektedir. Endojen apoptosis inhibitör proteini antogonisti ikinci mitokondri kökenli kaspaz aktivatörlerini taklit eden apoptosis inhibitör proteininin küçük moleküllü inhibitörleri SMAC mimetikleri olarak adlandırılır. AT-406, XIAP’ı ve cIAP-1/2’yi etkili şekilde hedefleyen oral olarak aktif bir SMAC mimetiğidir. Çeşitli insan kanser hücre hatları ile ilgili araştırmalarda kanser hücresi gelişimini yüksek etkinlikle baskıladığı belirtilmektedir. Fare, sıçan, insan olmayan primatlarda ve köpeklerde yapılmış in vivo ksenograft tümör araştırmalarında apoptozisi indüklediği gösterilmiştir. Günümüzde AT-406, insan kanser tedavisi için faz-I/II klinik denemelerinde araştırılmaktadır. Derlemede, AT-406 ile yapılmış farklı kanser hücre tipleriyle ilgili çalışmalar hakkında bilgiler verilmesi amaçlanmıştır

Anahtar Kelimeler

AT-406, SMAC mimetiği, IAP proteinleri, Antikanser, Proapoptotik

Kaynakça

• Wang J, Li W. Discovery of novel second mitochondria- derived activator of caspase mimetics as selective inhibitor of apoptosis protein inhibitors. J Pharmacol Exp Ther 2014; 349:319-29.
• Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol 2007; 35(4):495-516.
• Martinez-Ruiz G, Maldonado V, Ceballos-Cancino G, Grajeda JP, Melendez-Zajgla J. Role of Smac/DIABLO in cancer progression. J Exp Clin Cancer Res 2008;27:48.
• Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 2012; 11(2):109-24.
• Hunter AM, LaCasse EC, Korneluk RG. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 2007; 12(9):1543-68.
• Brunckhorst MK, Lerner D, Wang S, Yu Q. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther 2012; 13(9):804-11.
• Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem 2011; 54(8):2714-26.
• Derakhshan A, Chen Z, Van Waes C. Therapeutic small molecules target inhibitor of apoptosis proteins in cancers with deregulation of extrinsic and intrinsic cell death pathways. Clin Cancer Res 2017; 23(6):1379-87.
• Dubrez L, Berthelet J, Glorian V. IAP proteins as targets for drug development in oncology. Onco Targets Ther 2013; 9:1285-304.
• Philchenkov A, Miura K. The IAP Protein family, SMAC mimetics and cancer treatment. Crit Rev Oncog 2016; 21(3-4):185-202.
• Vucic D, Fairbrother WJ. The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clinical Cancer Research 2007; 3(20):5995-6000.
• Bai L, Smith DC, Wang S. Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacology & Therapeutics 2014; 144(1):82-95.
• Sun H, Nikolovska-Coleska Z, Yang CY, Qian D, Lu J, Qiu S. Design of small-molecule peptidic and nonpeptidic Smac mimetics. Acc Chem Res 2008; 41(10):1264-77.
• Fulda S. Promises and challenges of smac mimetics as cancer therapeutics. Clin Cancer Res 2015; 21(22):5030-6.
• Matzinger O, Viertl D, Tsoutsou P, Kadi L, Rigotti S, Zanna C. The radiosensitizing activity of the SMAC- mimetic, Debio 1143, is TNF-α-mediated in head and neck squamous cell carcinoma. Radiother Oncol 2015; 116(3):495-503.
• Lu J, Qin Q, Zhan LL, Liu J, Zhu HC, Yang X. AT- 406, an IAP inhibitor, activates apoptosis and induces radiosensitization of normoxic and hypoxic cervical cancer cells. J Pharmacol Sci 2014; 126(1):56-65.
• Langdon CG, Wiedemann N, Held MA, Mamillapalli R, Iyidogan P, Theodosakis N, Platt JT, Levy F, Vuagniaux G, Wang S, Bosenberg MW, Stern DF. SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells. Oncotarget 2015; 6(35):37410-25.
• Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol Med 2002; 8(8):385-9.
• Fristedt Duvefelt C, Lub S, Agarwal P, Arngården L, Hammarberg A, Maes K, Van Valckenborgh E, Vanderkerken K, Jernberg Wiklund H. Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2-implications for a combinatorial treatment. Oncotarget 2015; 6(24):20621-35.
• Fulda S. Targeting c-FLICE-like inhibitory protein (CFLAR) in cancer. Expert Opin Ther Targets 2013; 17(2):195-201.
• Huang Y, Yang X, Xu T, Kong Q, Zhang Y, Shen Y, Wei Y, Wang G, Chang KJ. Overcoming resistance to TRAIL- induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs. Int J Oncol 2016; 49(1):153-63.
• Hurwitz HI, Smith DC, Pitot HC, Brill JM, Chugh R, Rouits E, Rubin J, Strickler J, Vuagniaux G, Sorensen JM, Zanna C. Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT- 406) in patients with advanced cancer: Results of a first- in-man study. Cancer Chemother Pharmacol 2015; 75(4):851-9.