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:10.1007/510637-005-4827-3

Cited by 4 publications

(5 citation statements)

References 10 publications

(8 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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, 2014b; Haddad 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 Lilly and Company, 2018b, 2019b; Hamid et al, 2014).…”

Section: Targeting Rbm39 In Cancermentioning

confidence: 99%

“…Otherwise, these drugs were well tolerated in patients, and the most common dose‐limiting toxicities (DLTs) 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, 2019a, 2019b; Fujiwara 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 trials of indisulam, two trials of CQS and 11 trials of tasisulam (Tables 1 and S1).…”

Section: Targeting Rbm39 In Cancermentioning

confidence: 99%

See 1 more Smart Citation

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

Nijhuis

Keun

2021

British J Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Section: Targeting Rbm39 In Cancermentioning

confidence: 99%

Section: Targeting Rbm39 In Cancermentioning

confidence: 99%

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

Nijhuis

Keun

2021

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Currently, there are two major types of medications that specially aim at the interactions between substrates and recognition receptors in order to exert anti-cancer impacts, namely sulfonamides and thalidomide derivatives, each characterized by specific mechanisms. Three members of anticancer sulfonamides E7820, CQS (chloroquinoxaline sulfonamide) and indisulam have displayed efficacy against various cancers, including colorectal cancer and melanoma [244][245][246] . However, their mechanisms of action remain poorly defined.…”

Section: Perspective and Therapeutic Implicationsmentioning

confidence: 99%

The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

Cheng

Guo

North

et al. 2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

View full text Add to dashboard Cite

As a member of the Cullin-RING ligase family, Cullin-RING ligase 4 (CRL4) has drawn much attention due to its broad regulatory roles under physiological and pathological conditions, especially in neoplastic events. Based on evidence from knockout and transgenic mouse models, human clinical data, and biochemical interactions, we summarize the distinct roles of the CRL4 E3 ligase complexes in tumorigenesis, which appears to be tissue-and context-dependent. Notably, targeting CRL4 has recently emerged as a noval anti-cancer strategy, including thalidomide and its derivatives that bind to the substrate recognition receptor cereblon (CRBN), and anticancer sulfonamides that target DCAF15 to suppress the neoplastic proliferation of multiple myeloma and colorectal cancers, respectively. To this end, PROTACs have been developed as a group of engineered bi-functional chemical glues that induce the ubiquitinationmediated degradation of substrates via recruiting E3 ligases, such as CRL4 (CRBN) and CRL2 (pVHL). We summarize the recent major advances in the CRL4 research field towards understanding its involvement in tumorigenesis and further discuss its clinical implications. The anti-tumor effects using the PROTAC approach to target the degradation of undruggable targets are also highlighted.

show abstract

“…XK469 (NSC 697887) and CQS (NSC 339004), two synthetic quinoxaline derivatives without two oxygens on the quinoxaline ring, also show solid tumor selectivity. XK469 and CQS have entered Phase I and Phase II clinical study, respectively ( Miller et al, 1997 ; Bekaii-Saab et al, 2006 ; Alousi et al, 2007 ). Gao et al (1999) reported the primary target of XK469 is Topo IIβ, and CQS was found to be both a Topo-IIα and a Topo-IIβ poison ( Gao et al, 2000 ).…”

Section: Antitumor Activity Of Qdnosmentioning

confidence: 99%

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Cheng

Cao

et al. 2016

Front. Pharmacol.

View full text Add to dashboard Cite

Quinoxaline 1,4-di-N-oxides (QdNOs) have manifold biological properties, including antimicrobial, antitumoral, antitrypanosomal and antiinflammatory/antioxidant activities. These diverse activities endow them broad applications and prospects in human and veterinary medicines. As QdNOs arouse widespread interest, the evaluation of their medicinal chemistry is still in progress. In the meantime, adverse effects have been reported in some of the QdNO derivatives. For example, genotoxicity and bacterial resistance have been found in QdNO antibacterial growth promoters, conferring urgent need for discovery of new QdNO drugs. However, the modes of actions of QdNOs are not fully understood, hindering the development and innovation of these promising compounds. Here, QdNOs are categorized based on the activities and usages, among which the antimicrobial activities are consist of antibacterial, antimycobacterial and anticandida activities, and the antiprotozoal activities include antitrypanosomal, antimalarial, antitrichomonas, and antiamoebic activities. The structure-activity relationship and the mode of actions of each type of activity of QdNOs are summarized, and the toxicity and the underlying mechanisms are also discussed, providing insight for the future research and development of these fascinating compounds.

show abstract

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 4 publications

References 10 publications

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

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

The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions

Contact Info

Product

Resources

About