A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC)

Bekaii‐Saab, Tanios; Mortazavi, Amir; Hicks, Lee G.; Zalupski, Mark M.; Pelley, Robert J.; Chan, Kenneth K.; Kraut, Eric H.

doi:10.1007/s10637-005-4827-3

Cited by 13 publications

(6 citation statements)

References 9 publications

(11 reference statements)

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“…Like indisulam, tasisulam and chloroquinoxaline sulfonamide (CQS) are aryl sulfonamides with anti-cancer activity that have been used in clinical trials for the treatment of solid tumors (Fig. 5A) (32)(33)(34)(35)(36)(37). On the basis of their structural similarity to indisulam, we hypothesized that tasisulam and CQS might also recruit RBM39 to DCAF15.…”

Section: Other Clinically Tested Sulfonamides Exhibit the Same Mechan...mentioning

confidence: 99%

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Han

Goralski

Gaskill

et al. 2017

Science

496

542

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Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing. Many cancer cell lines derived from hematopoietic and lymphoid lineages are sensitive to indisulam, and their sensitivity correlates with DCAF15 expression levels. Two other clinically tested sulfonamides, tasisulam and chloroquinoxaline sulfonamide, share the same mechanism of action as indisulam. We propose that DCAF15 expression may be a useful biomarker to guide clinical trials of this class of drugs, which we refer to as SPLAMs (splicing inhibitor sulfonamides).

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Section: Other Clinically Tested Sulfonamides Exhibit the Same Mechan...mentioning

confidence: 99%

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Han

Goralski

Gaskill

et al. 2017

Science

496

542

View full text Add to dashboard Cite

show abstract

“…The drugs were used either as single agents (66%) or in combination with existing chemotherapies (34%). While most trials completed as planned, three trials of indisulam and one trial of CQS terminated prematurely due to a lack of efficacy (Bekaii-Saab et al, 2006;Eisai Inc., 2014a, 2014bHaddad et al, 2004). Meanwhile, tasisulam treatment was associated with unexpected patient deaths, which led to early termination of three trials including one phase III trial with advanced melanoma patients (Eli Company, 2018b, 2019b;Hamid et al, 2014).…”

Section: Aryl Sulphonamides In Clinical Trialsmentioning

confidence: 99%

“…were neutropenia and thrombocytopenia (Table S1). Study results from 34 trials are available to this date (Assi et al, 2018;Bekaii-Saab et al, 2006;Conley et al, 1995;Dittrich et al, 2003;Dittrich et al, 2007;Eli Lilly and Company, 2018a, 2018b, 2018c, 2018d, 2018e, 2018f, 2019aFujiwara et al, 2013;Gordon et al, 2013;Haddad et al, 2004;Hamid et al, 2014;Jotte et al, 2015;Kirkwood et al, 2011;Miller et al, 1997;Milojkovic Kerklaan et al, 2016;Mita et al, 2011;Punt et al, 2001;Raymond et al, 2002;Rigas et al, 1992;Rigas et al, 1995;Ryan et al, 2013;Scagliotti et al, 2012;Siegel-Lakhai et al, 2008;Simon et al, 2011;Smyth et al, 2005;Talbot et al, 2007;Terret et al, 2003;Yamada et al, 2005). No complete responses were observed, but a small number of patients had partial tumour regression (partial response) in four 1 and S1).…”

Section: Aryl Sulphonamides In Clinical Trialsmentioning

confidence: 99%

RNA‐binding motif protein 39 (RBM39): An emerging cancer target

Nijhuis

Keun

2021

British J Pharmacology

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RNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in transcriptional co-regulation and alternative RNA splicing. Recent studies have revealed that RBM39 is the unexpected target of aryl sulphonamides, which act as molecular glues between RBM39 and the DCAF15-associated E3 ubiquitin ligase complex leading to selective degradation of the target. Loss of RBM39 leads to aberrant splicing events and differential gene expression, thereby inhibiting cell cycle progression and causing tumour regression in a number of preclinical models. Many clinical studies have shown that aryl sulphonamides were well tolerated, but their clinical performance was limited due to an insufficient understanding of the target, RBM39 biology and a lack of predictive biomarkers. This review summarises the current knowledge of RBM39 function and discusses the therapeutic potential of this spliceosome target in cancer therapy.

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“…( A ) Structures of CDDO-Me 56,57 and CDDO-JQ1. 66 ( B ) Structures of sulfonamide derivatives, indisulam, 67 E7820, 68 CQS, 69 and DP1. 78 ( C ) Structure of CCW 28-3.…”

Section: Introductionmentioning

confidence: 99%

“…Sulfonamide derivatives indisulam (E7070), 67 E7820, 68 and chloroquinoxaline sulfonamide (CQS) 69 were found to have antitumor activity and were tested in the clinic for the treatment of cancers ( Fig. 5B ).…”

Section: Introductionmentioning

confidence: 99%

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

2021

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Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand and treat human disease. A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin–proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands, notably for von Hippel–Lindau (VHL) and cereblon (CRBN), revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity. A first wave of PROTAC drugs are now undergoing clinical development in cancer, and the field is seeking to extend the repertoire of chemistries that allow hijacking new E3 ligases to improve the scope of targeted protein degradation. Here, we briefly review how traditional E3 ligase ligands were discovered, and then outline approaches and ligands that have been recently used to discover new E3 ligases for PROTACs. We will then take an outlook at current and future strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of DNA-encoded libraries (DELs), display technologies and cyclic peptides, smaller molecular glue degraders, and covalent warhead ligands. These approaches are ripe for expanding the chemical space of PROTACs and usher in the advent of other emerging bifunctional modalities of proximity-based pharmacology.

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A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC)

Abstract: CQS, when given at a dose of 2000 mg/m2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.

Cited by 13 publications

References 9 publications

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15

RNA‐binding motif protein 39 (RBM39): An emerging cancer target

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

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