APOPTOSIS ENHANCERS

IAP inhibition

Inhibitor of apoptosis proteins (IAPs) are frequently overexpressed in tumors, 1-6 including squamous cell carcinoma of the head and neck (SCCHN), and have been shown to increase the resistance of cancer cells to apoptosis and prevent cell death induced by anticancer treatments.7-10

IAPs block apoptosis by preventing activation of caspases and suppressing the release of inflammatory cytokines via intrinsic and extrinsic apoptotic pathways.11-15 Inhibition of IAPs is thought to release this blockade and thereby restore cancer cell sensitivity to apoptosis.11,12,14 Therefore, targeting IAPs is being investigated as a potential approach, especially in combination with cell death-inducing therapies, such as chemotherapy (CT) or radiotherapy (RT).

Xevinapant – IAP inhibitor

Description

Xevinapant (formerly known as Debio 1143) is a potential first-in-class, investigational, oral, small-molecule IAP inhibitor, designed to restore cancer cell sensitivity to apoptosis and thereby enhance the effects of CT and RT.4,5,16-20

IAP

CLINICAL TRIALS

VIEWPOINTS ON CANCER

Investigational compounds are not approved by any health authority. Safety and efficacy have not been established.

Abbreviations:
cIAP, cellular inhibitor of apoptosis protein; CRT, chemoradiotherapy; CT, chemotherapy; FADD, Fas-associated protein with death domain; IAP, inhibitor of apoptosis protein; RIP1, receptor-interacting serine/threonine-protein kinase 1; RT, radiotherapy; SMAC, second mitochondria-derived activator of caspases; TNF, tumour necrosis factor; XIAP, X-linked inhibitor of apoptosis proteins.

References:

  1. Vucic D. Targeting IAP (inhibitor of apoptosis) proteins for therapeutic intervention in tumors. Curr Cancer Drug Targets. 2008;8(2):110-117. 
  2. Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov. 2012;11(2):109-124. 
  3. Michie J, Kearney CJ, Hawkins ED, Silke J, Oliaro J. The immuno-modulatory effects of inhibitor of apoptosis protein antagonists in cancer immunotherapy. Cells. 2020;9(1):207. 
  4. 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):804-811. 
  5. Serova M, Tijeras-Raballand A, Albert S, et al. Effects of Debio 1143, a novel oral IAP inhibitor, in monotherapy and in combination with platinum drugs in human SCCHN tumor specimens. Cancer Res. 2014;74(suppl 19). Abstract 2752.
  6. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-582. 
  7. Rathore R, McCallum JE, Varghese E, Florea AM, Büsselberg D. Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis. 2017;22(7):898-919. 
  8. Dubrez L, Berthelet J, Glorian V. IAP proteins as targets for drug development in oncology. Onco Targets Ther. 2013;9:1285-1304. 
  9. Vucic D, Fairbrother WJ. The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res. 2007;13(20):5995-6000. 
  10. Fulda S. Targeting IAP proteins in combination with radiotherapy. Radiat Oncol. 2015;10:105.
  11. Duckett CS. IAP proteins: sticking it to Smac. Biochem J. 2005;385(Pt 1):e1-e2. 
  12. Abbas R, Larisch S. Targeting XIAP for promoting cancer cell death-the story of ARTS and SMAC. Cells. 2020;9(3):663. 
  13. Obexer P, Ausserlechner MJ. X-linked inhibitor of apoptosis protein - a critical death resistance regulator and therapeutic target for personalized cancer therapy. Front Oncol. 2014;4:197. 
  14. Zhao XY, Wang XY, Wei QY, Xu YM, Lau ATY. Potency and selectivity of SMAC/DIABLO mimetics in solid tumor therapy. Cells. 2020;9(4):1012. 
  15. Sun SC. Non-canonical NF-κB signaling pathway. Cell Res. 2011;21(1):71-85. 
  16. Cai Q, Sun H, Peng Y, 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):2714-2726. 
  17. Matzinger O, Viertl D, Tsoutsou P, et al. The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma. Radiother Oncol. 2015;116(3):495-503. 
  18. Thibault B, Genre L, Le Naour A, et al. DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death. Sci Rep. 2018;8(1):17862. 
  19. Gomez-Roca C, Evan C, Le Tourneau C, et al. Open-label, non-randomized, exploratory pre-operative window-of-opportunity trial to investigate the pharmacokinetics and pharmacodynamics of the smac mimetic Debio 1143 in patients with resectable squamous cell carcinoma of the head and neck. Cancer Res. 2019;79(suppl 13). Abstract 5001.
  20. Viertl D, Perillo-Adamer F, Rigotti S, et al. The SMAC-mimetic Debio 1143 efficiently enhanced chemo and radiotherapy in head and neck squamous cell carcinoma models. Cancer Res. 2013;73(supply 8). Abstract 2055.