This phase I/Ib trial tests the safety, side effects, best dose, and effectiveness of ASTX660 (tolinapant) in combination with eribulin mesylate (eribulin) in treating patients with triple negative breast cancer that cannot be removed by surgery (unresectable) or that has spread to nearby tissues or lymph nodes (locally advanced) or to other places in the body (metastatic). Tolinapant may stop the growth of tumor cells by blocking proteins, such as XIAP and cIAP1, needed for tumor cell survival. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tolinapant in combination with eribulin may be safe, tolerable, and/or effective in treating patients with unresectable, locally advanced, or metastatic triple negative breast cancer.

Start Date08 Nov 2024

Sponsor / Collaborator

National Cancer Institute

NCT06393751 / Not yet recruitingPhase 1/2IIT

A Randomized Phase 1/2 Trial Evaluating the Addition of Tolinapant to Weekly Paclitaxel With or Without Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer

This phase I/II trial tests the safety, best dose and effectiveness of adding tolinapant (ASTX660) to paclitaxel with or without bevacizumab in treating patients with ovarian cancer that has come back after a period of improvement (recurrent). Tolinapant may stop the growth of tumor cells by blocking proteins, such as XIAP and cIAP1, that promote the growth of tumor cells and increase resistance to chemotherapy. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to the tumor. This may slow the growth and spread of tumor cells. Adding ASTX660 to paclitaxel with or without bevacizumab may be safe, tolerable and/or effective in treating patients with recurrent ovarian cancer.

Start Date01 Nov 2024

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with XIAP x cIAP1

100 Translational Medicine associated with XIAP x cIAP1

0 Patents (Medical) associated with XIAP x cIAP1

525

Literatures (Medical) associated with XIAP x cIAP1

01 Dec 2024·Pharmacology Research & Perspectives

The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy

Article

Author: Reader, Mike ; Martins, Vanessa ; Ward, George ; Johnson, Chris ; Smyth, Tomoko ; Wilsher, Nicola ; Chessari, Gianni

AbstractAT‐IAP (1‐{6‐[(4‐fluorophenyl)methyl]‐3,3‐dimethyl‐1H,2H,3H‐pyrrolo[3,2‐b]pyridin‐1‐yl}‐2‐[(2R,5R)‐5‐methyl‐2‐{[(3R)‐3‐methylmorpholin‐4‐yl]methyl}piperazin‐1‐yl]ethan‐1‐one) was identified as a novel potent non‐alanine small molecule dual inhibitor of cIAP1/XIAP protein. AT‐IAP was assessed in preclinical species, demonstrating favorable bioavailability in rodent species and oral efficacy at 30 mg/kg in MDA‐MB‐231 mouse xenograft models. The major metabolic route of AT‐IAP was identified to be CYP3A driven, resulting in low oral exposure in non‐human primate (NHP) studies, given the comparatively high expression of equivalent CYP3A. AT‐IAP metabolite identification studies determined ring opening of the morpholino or piperazine moiety. An extensive campaign of optimisation resulted in increased polarity by the addition of a hydroxymethyl, which led to the identification of tolinapant (1‐(6‐[(4‐Fluorophenyl)methyl]‐5‐(hydroxymethyl)‐3,3‐dimethyl‐1 H,2 H,3 H‐pyrrolo[3,2‐ b]pyridin‐1‐yl)‐2‐[(2 R,5 R)‐5‐methyl‐2‐([(3R)‐3‐methylmorpholin‐4‐yl]methyl)piperazin‐1‐yl]ethan‐1‐one) with reduced CYP3A metabolism. Tolinapant showed oral bioavailability in rodents and NHP in the range 12–34% at 5 mg/kg. Non‐linear pharmacokinetics in NHP were observed at oral doses in the range 5–75 mg/kg. Pharmacodynamic modulation and efficacy were demonstrated in A375 mouse xenograft models at dose ranges between 5 and 20 mg/kg. On‐target engagement, as measured by reduction of cIAP 1 protein levels, was confirmed in NHP surrogate tissues and applied to target activity assessments in tolinapant phase1/2 clinical trials.

01 Sep 2024·European Journal of Pharmacology

An 8-aminoquinoline-naphthyl copper complex causes apoptotic cell death by modulating the expression of apoptotic regulatory proteins in breast cancer cells

Article

Author: Myeza, Nonzuzo ; Slabber, Cathy ; Munro, Orde Q ; Martins-Furness, Carla ; Harmse, Leonie ; Zacharias, Savannah C ; Sookai, Sheldon

Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted therapy, including monoclonal antibodies and kinase inhibitors, drug resistance and treatment failure remain a common occurrence. Copper, complexed to various organic ligands, has gained attention as potential chemotherapeutic agents due to its perceived decreased toxicity to normal cells. The cytotoxic efficacy and the mechanism of cell death of an 8-aminoquinoline-naphthyl copper complex (Cu8AqN) in MCF-7 and MDA-MB-231 breast cancer cell lines was investigated. The complex inhibited the growth of MCF-7 and MDA-MB-231 cells with IC₅₀ values of 2.54 ± 0.69 μM and 3.31 ± 0.06 μM, respectively. Nuclear fragmentation, annexin V binding, and increased caspase-3/7 activity indicated apoptotic cell death. The loss of mitochondrial membrane potential, an increase in caspase-9 activity, the absence of active caspase-8 and a decrease of tumour necrosis factor receptor 1(TNFR1) expression supported activation of the intrinsic apoptotic pathway. Increased ROS formation and increased expression of haem oxygenase-1 (HMOX-1) indicated activation of cellular stress pathways. Expression of p21 protein in the nuclei was increased indicating cell cycle arrest, whilst the expression of inhibitor of apoptosis proteins (IAPs); cIAP1, XIAP and survivin were decreased, creating a pro-apoptotic environment. Phosphorylated p53 species; phospho-p53(S15), phospho-p53(S46), and phospho-p53(S392) accumulated in MCF-7 cells indicating the potential of Cu8AqN to restore p53 function in the cells. In combination, the data indicates that Cu8AqN is a useful lead molecule worthy of further exploration as a potential anti-cancer drug.

01 Jul 2024·Journal of Biological Chemistry

USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells

Article

Author: Zhu, Shan ; Zou, Shan-Shan ; Gao, Bao ; Chen, Jingtao ; Qiao, Yuan ; Liu, Yong-Jun ; Yang, Ning

Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.

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