Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway

Federica Cossu; Simone Camelliti; Daniele Lecis; Luca Sorrentino; Maria Teresa Majorini; Mario Milani; Eloise Mastrangelo

doi:10.1016/j.csbj.2021.11.034

Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway

Comput Struct Biotechnol J. 2021 Nov 26:19:6366-6374. doi: 10.1016/j.csbj.2021.11.034. eCollection 2021.

Authors

Federica Cossu¹, Simone Camelliti^{1

2}, Daniele Lecis², Luca Sorrentino^{1

3}, Maria Teresa Majorini², Mario Milani¹, Eloise Mastrangelo¹

Affiliations

¹ CNR-IBF, Consiglio Nazionale delle Ricerche - Istituto di Biofisica, Via Celoria, 26, I-20133 Milan, Italy.
² Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo, 42, I-20133, Milano, Italy.
³ Dipartimento di Chimica, Università di Milano, Via Venezian, 21, I-20133 Milano, Italy.

Abstract

Inhibitors of apoptosis proteins (IAPs) are validated onco-targets, as their overexpression correlates with cancer onset, progression, diffusion and chemoresistance. IAPs regulate cell death survival pathways, inflammation, and immunity. Targeting IAPs, by impairing their protein-protein interaction surfaces, can affect events occurring at different stages of cancer development. To this purpose, we employed a rational virtual screening approach to identify compounds predicted to interfere with the assembly of pro-survival macromolecular complexes. One of the candidates, FC2, was shown to bind in vitro the BIR1 domains of both XIAP and cIAP2. Moreover, we demonstrated that FC2 can induce cancer cell death as a single agent and, more potently, in combination with the Smac-mimetic SM83 or with the cytokine TNF. FC2 determined a prolonged activation of the NF-κB pathway, accompanied to a stabilization of XIAP-TAB1 complex. This candidate molecule represents a valuable lead compound for the development of a new class of IAP-antagonists for cancer treatment.

Keywords: BIR, baculoviral IAP repeat; Baculoviral IAP repeat; Drug discovery; IAP, inhibitor of apoptosis proteins; IAP-antagonist; Inhibitor of apoptosis proteins; NF-kB; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; SM, Smac-mimetic; TAB, TAK1 binding protein; TAK1, (TGFβ)-activated kinase; TGFβ, transforming growth factor-β; TNF, tumor necrosis factor; TRAF, TNF receptor associated factor; Virtual screening.