Top

Published in:

Open Access 01-10-2020 | PRECLINICAL STUDIES

Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists

Authors: Agnieszka Łupicka-Słowik, Mateusz Psurski, Renata Grzywa, Monika Cuprych, Jarosław Ciekot, Waldemar Goldeman, Elżbieta Wojaczyńska, Jacek Wojaczyński, Józef Oleksyszyn, Marcin Sieńczyk

Published in: Investigational New Drugs | Issue 5/2020

Summary

One of the strategies employed by novel anticancer therapies is to put the process of apoptosis back on track by blocking the interaction between inhibitor of apoptosis proteins (IAPs) and caspases. The activity of caspases is modulated by the caspases themselves in a caspase/procaspase proteolytic cascade and by their interaction with IAPs. Caspases can be released from the inhibitory influence of IAPs by proapoptotic proteins such as secondary mitochondrial activator of caspases (Smac) that share an IAP binding motif (IBM). The main purpose of the present study was the design and synthesis of phosphorus-based peptidyl antagonists of IAPs that mimic the endogenous Smac protein, which blocks the interaction between IAPs and caspases. Based on the structure of the IAP antagonist and recently reported thiadiazole derivatives, we designed and evaluated the biochemical properties of a series of phosphonic peptides bearing the N-Me-Ala-Val/Chg-Pro-OH motif (Chg: cyclohexylglycine). The ability of the obtained compounds to interact with the binding groove of the X-linked inhibitor of apoptosis protein baculovirus inhibitor of apoptosis protein repeat (XIAP BIR3) domain was examined by a fluorescence polarization assay, while their potential to induce autoubiquitination followed by proteasomal degradation of cellular IAP1 was examined using the MDA-MB-231 breast cancer cell line. The highest potency against BIR3 was observed among peptides containing C-terminal phosphonic phenylalanine analogs, which displayed nanomolar K_i values. Their antiproliferative potential as well as their proapoptotic action, manifested by an increase in caspase-3 activity, was examined using various cell lines.

Available only for authorised users

Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516. https://doi.org/10.1080/01926230701320337CrossRefPubMedPubMedCentral

Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87. https://doi.org/10.1186/1756-9966-30-87CrossRefPubMedPubMedCentral

Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–129. https://doi.org/10.1038/35040009CrossRefPubMed

Krijnen PA, Simsek S, Niessen HW (2009) Apoptosis in diabetes. Apoptosis 14:1387–1388. https://doi.org/10.1007/s10495-009-0419-6CrossRefPubMedPubMedCentral

Chang HY, Yang X (2000) Proteases for cell suicide: functions and regulation of caspases. Microbiol Mol Biol Rev 64:821–846CrossRefPubMedPubMedCentral

Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16CrossRefPubMedPubMedCentral

Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241. https://doi.org/10.1038/nrm2312CrossRefPubMed

Ichim G, Tait SW (2016) A fate worse than death: apoptosis as an oncogenic process. Nat Rev Cancer 16:539–548. https://doi.org/10.1038/nrc.2016.58CrossRefPubMed

Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63. https://doi.org/10.1038/nrm3722CrossRefPubMed

10.

Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632. https://doi.org/10.1038/nrm2952CrossRefPubMed

11.

McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5:a008656. https://doi.org/10.1101/cshperspect.a008656CrossRefPubMedPubMedCentral

12.

Silke J, Meier P (2013) Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harb Perspect Biol 5:a008730. https://doi.org/10.1101/cshperspect.a008730CrossRefPubMedPubMedCentral

13.

Verhagen AM, Coulson EJ, Vaux DL (2001) Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol 2:reviews3009.1. https://doi.org/10.1186/gb-2001-2-7-reviews3009CrossRef

14.

Clem RJ, Miller LK (1994) Control of programmed cell death by the baculovirus genes p35 and iap. Mol Cell Biol 14:5212–5222CrossRefPubMedPubMedCentral

15.

Crook NE, Clem RJ, Miller LK (1993) An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67:2168–2174CrossRefPubMedPubMedCentral

16.

Silke J, Kratina T, Chu D et al (2005) Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance. PNAS 102:16182–16187. https://doi.org/10.1073/pnas.0502828102CrossRefPubMedPubMedCentral

17.

Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11:109–124. https://doi.org/10.1038/nrd3627CrossRefPubMed

18.

de Almagro MC, Vucic D (2012) The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol 34:200–211PubMed

19.

Liu B, Han M, Wen JK, Wang L (2007) Livin/ML-IAP as a new target for cancer treatment. Cancer Lett 250:168–176. https://doi.org/10.1016/j.canlet.2006.09.024CrossRefPubMed

20.

Kocab AJ, Duckett CS (2016) Inhibitor of apoptosis proteins as intracellular signalling intermediates. FEBS J 283:221–231. https://doi.org/10.1111/febs.13554CrossRefPubMed

21.

Cossu F, Milani M, Mastrangelo E, Lecis D (2019) Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment. Comput Struct Biotechnol J 17:142–150. https://doi.org/10.1016/j.csbj.2019.01.009CrossRefPubMedPubMedCentral

22.

Krajewska M, Krajewski S, Banares S et al (2003) Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res 9:4914–4925PubMed

23.

Hofmann HS, Simm A, Hammer A, Silber RE, Bartling B (2002) Expression of inhibitors of apoptosis (IAP) proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol 128:554–560. https://doi.org/10.1007/s00432-002-0364-zCrossRefPubMed

24.

Krepela E, Dankova P, Moravcikova E et al (2009) Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma. Int J Oncol 35:1449–1462CrossRefPubMed

25.

Carter BZ, Gronda M, Wang Z et al (2005) Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 105:4043–4050. https://doi.org/10.1182/blood-2004-08-3168CrossRefPubMedPubMedCentral

26.

Nakagawa Y, Hasegawa M, Kurata M et al (2005) Expression of IAP-family proteins in adult acute mixed lineage leukemia (AMLL). Am J Hematol 78:173–180. https://doi.org/10.1002/ajh.20285CrossRefPubMed

27.

Flanagan L, Kehoe J, Fay J et al (2015) High levels of X-linked Inhibitor-of-Apoptosis Protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer. Radiat Oncol 10:131. https://doi.org/10.1186/s13014-015-0437-1CrossRefPubMedPubMedCentral

28.

Shiozaki EN, Chai J, Rigotti DJ et al (2003) Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell 11:519–527CrossRefPubMed

29.

Scott FL, Denault J-B, Riedl SJ et al (2005) XIAP inhibits caspase-3 and – 7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J 24:645–655. https://doi.org/10.1038/sj.emboj.7600544CrossRefPubMedPubMedCentral

30.

Liu Z, Sun C, Olejniczak ET et al (2000) Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408:1004–1008. https://doi.org/10.1038/35050006CrossRefPubMed

31.

Wu G, Chai J, Suber TL et al (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature 408:1008–1012. https://doi.org/10.1038/35050012CrossRefPubMed

32.

Rathore R, McCallum JE, Varghese E, Florea AM, Busselberg D (2017) Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis 22:898–919. https://doi.org/10.1007/s10495-017-1375-1CrossRefPubMedPubMedCentral

33.

Cong H, Xu L, Wu Y et al (2019) Inhibitor of Apoptosis Protein (IAP) Antagonists in anticancer agent discovery: current status and perspectives. J Med Chem 62:5750–5772. https://doi.org/10.1021/acs.jmedchem.8b01668CrossRefPubMed

34.

Sun H, Nikolovska-Coleska Z, Yang CY et al (2008) Design of small-molecule peptidic and nonpeptidic Smac mimetics. Acc Chem Res 41:1264–1277. https://doi.org/10.1021/ar8000553CrossRefPubMedPubMedCentral

35.

Cai Q, Sun H, Peng Y et al (2011) 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 54:2714–2726. https://doi.org/10.1021/jm101505dCrossRefPubMedPubMedCentral

36.

Qin Q, Zuo Y, Yang X et al (2014) Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. Tumour Biol 35:2565–2574. https://doi.org/10.1007/s13277-013-1338-2CrossRefPubMed

37.

Yang C, Wang H, Zhang B et al (2016) LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC. J Exp Clin Cancer Res 35:158. https://doi.org/10.1186/s13046-016-0435-7CrossRefPubMedPubMedCentral

38.

Flygare JA, Beresini M, Budha N et al (2012) The discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J Med Chem 55:4101–4113. https://doi.org/10.1021/jm300060kCrossRefPubMedPubMedCentral

39.

Tchoghandjian A, Soubéran A, Tabouret E et al (2016) Inhibitor of apoptosis protein expression in glioblastomas and their in vitro and in vivo targeting by SMAC mimetic GDC-0152. Cell Death Dis 7:e2325. https://doi.org/10.1038/cddis.2016.214CrossRefPubMedPubMedCentral

40.

Wong H, Gould SE, Budha N et al (2013) Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist. Drug Metab Dispos 41:2104–2113. https://doi.org/10.1124/dmd.113.053926CrossRefPubMed

41.

Hird AW, Aquila BM, Hennessy EJ, Vasbinder MM, Yang B (2015) Small molecule inhibitor of apoptosis proteins antagonists: a patent review. Expert Opin Ther Pat 25:755–774. https://doi.org/10.1517/13543776.2015.1041922CrossRefPubMed

42.

Infante JR, Dees EC, Olszanski AJ et al (2014) Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:3103–3110. https://doi.org/10.1200/JCO.2013.52.3993CrossRefPubMed

43.

Cohen F, Alicke B, Elliott LO et al (2009) Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold. J Med Chem 52:1723–1730. https://doi.org/10.1021/jm801450cCrossRefPubMed

44.

Franklin MC, Kadkhodayan S, Ackerly H et al (2003) Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP). Biochemistry 42:8223–8231. https://doi.org/10.1021/bi034227tCrossRefPubMed

45.

Deshayes K, Murray J, Vucic D (2012) The development of small-molecule IAP antagonists for the treatment of cancer. In: Wendt M (ed) Protein-protein interactions. Topics in medicinal chemistry. Springer, Berlin. https://doi.org/10.1007/978-3-642-28965-1_3

46.

Elsayed NMY, Abou El Ella DA, Serya RAT, Abouzid KAM (2015) Targeting apoptotic machinery as approach for anticancer therapy: Smac mimetics as anticancer agents. Future J Pharm Sci 1:16–21. https://doi.org/10.1016/j.fjps.2015.05.005CrossRef

47.

Chatterjee J, Gilon C, Hoffman A, Kessler H (2008) N-methylation of peptides: a new perspective in medicinal chemistry. Acc Chem Res 41:1331–1342. https://doi.org/10.1021/ar8000603CrossRefPubMed

48.

Li D, Elbert DL (2002) The kinetics of the removal of the N-methyltrityl (Mtt) group during the synthesis of branched peptides. J Pept Res 60:300–303CrossRefPubMed

49.

Oleksyszyn J (1981) Synthesis of N-Acylated 1-Aminoalkyl-Diphenylphosphine oxides by amidoalkylation of diphenylchlorophosphine. Synthesis-Stuttgart 444–445

50.

Zobel K, Wang L, Varfolomeev E et al (2006) Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs. ACS Chem Biol 1:525–533. https://doi.org/10.1021/cb600276qCrossRefPubMed

51.

Ross NT, Katt WP, Hamilton AD (2010) Synthetic mimetics of protein secondary structure domains. Phil Trans A Math Phys Eng Sci 368:989–1008. https://doi.org/10.1098/rsta.2009.0210CrossRef

52.

Finlay D, Vamos M, González-López M et al (2014) Small-molecule IAP antagonists sensitize cancer cells to TRAIL-induced apoptosis: roles of XIAP and cIAPs. Mol Cancer Ther 13:5–15. https://doi.org/10.1158/1535-7163.MCT-13-0153CrossRefPubMed

53.

ten Brink T, Exner TE (2010) pK(a) based protonation states and microspecies for protein-ligand docking. J Comput Aided Mol Des 24:935–942. https://doi.org/10.1007/s10822-010-9385-xCrossRefPubMed

54.

Korb O, Stützle T, Exner TE (2007) An ant colony optimization approach to flexible protein–ligand docking. Swarm Intell 1:115–134. https://doi.org/10.1007/s11721-007-0006-9CrossRef

55.

Soroka M, Iwańczyk D (2001) Method of obtaining triallylmethylamines. PL 339713 (A1) Patent

56.

Winiarski L, Oleksyszyn J, Sienczyk M (2012) Human neutrophil elastase phosphonic inhibitors with improved potency of action. J Med Chem 55:6541–6553. https://doi.org/10.1021/jm300599xCrossRefPubMed

57.

Oleksyszyn J, Subotkowska L, Mastalerz P (1979) Diphenyl 1-aminoalkanephosphonates. Synthesis 985–986

58.

Zhang JH, Chung TD, Oldenburg KR (1999) A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4:67–73. https://doi.org/10.1177/108705719900400206CrossRefPubMed

59.

Nikolovska-Coleska Z, Wang R, Fang X et al (2004) Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Anal Biochem 332:261–273. https://doi.org/10.1016/j.ab.2004.05.055CrossRefPubMed

60.

Skehan P, Storeng R, Scudiero D et al (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112. https://doi.org/10.1093/jnci/82.13.1107CrossRefPubMed

61.

Nevozhay D (2014) Cheburator software for automatically calculating drug inhibitory concentration from in vitro screening assays. PLoS One 9:e106186. https://doi.org/10.1371/journal.pone.0106186CrossRefPubMedPubMedCentral

62.

Psurski M, Janczewski Ł, Świtalska M et al (2017) Novel phosphonate analogs of sulforaphane: Synthesis, in vitro and in vivo anticancer activity. Eur J Med Chem 132:63–80. https://doi.org/10.1016/j.ejmech.2017.03.028CrossRefPubMed

Title: Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists
Authors: Agnieszka Łupicka-Słowik
Mateusz Psurski
Renata Grzywa
Monika Cuprych
Jarosław Ciekot
Waldemar Goldeman
Elżbieta Wojaczyńska
Jacek Wojaczyński
Józef Oleksyszyn
Marcin Sieńczyk
Publication date: 01-10-2020
Publisher: Springer US
Published in: Investigational New Drugs / Issue 5/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-020-00923-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 5/2020

Evaluating the antitumor activity of sphingosine-1-phosphate against human triple-negative breast cancer cells with basal-like morphology

First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors

Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients

Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir

W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors

Sorafenib may enhance antitumour efficacy in hepatocellular carcinoma patients by modulating the proportions and functions of natural killer cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer