Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

Tong, Wei; Chen, Rong; Plunkett, William; Siegel, David S.; Sinha, Rajni; Harvey, R. Donald; Badros, Ashraf; Popplewell, Leslie; Coutre, Steven; Fox, Judith A.; Mahadocon, Kristi; Chen, Tianling; Kegley, Peggy; Hoch, Ute; Wierda, William G.

doi:10.1200/jco.2009.26.1347

Cited by 188 publications

(145 citation statements)

References 29 publications

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“…10,35 While clinical studies have demonstrated the safety of using transcriptional repressors such as flavopiridol and SNS-032 that inhibit Cdks and block Mcl-1 expression, the limited clinical activity observed in patients with leukemias suggests that targeting Mcl-1 alone may only be effective in a subset of AML cases. 45,46 Our findings show that dual targeting of both PI3K and transcriptional kinases by PIK-75 demonstrates antileukemic activity in primary human AML cells without impacting on the survival, colonyforming potential, or engraftment capacity of nontransformed hematopoietic BM progenitors ( Figure 6). Thus, while PIK-75 targets 2 fundamental cell survival pathways, our data indicate that there is a therapeutic window that permits selective targeting of AML cells.…”

Section: Discussionmentioning

confidence: 98%

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Thomas

Powell

Vergez

et al. 2013

Blood

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Section: Discussionmentioning

confidence: 98%

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Thomas

Powell

Vergez

et al. 2013

Blood

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“…The best clinical response was stable disease in 3 (15%) patients (Heath et al 2008). Another phase I trial was performed in 19 patients with advanced chronic lymphocytic leukemia and multiple myeloma (Tong et al 2010). Major toxicity in that case was myelosuppression.…”

Section: Broad-range Inhibitorsmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

220

176

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Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

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“…A recent phase I study showed that BMS-387032 caused tumor lysis syndrome and myelosuppression. 48 In addition to the effect on p-TEFb, our data show that the CDK-related kinase PCTAIRE is a novel potently inhibited target of BMS-387032, but not flavopiridol, whereas the related kinase PFTAIRE is moderately inhibited by both drugs. A protein of unknown function encoded by C14ORF129 exhibits an inhibition dose response very similar to PCTAIRE and may represent a regulatory subunit of this kinase.…”

Section: Discussionmentioning

confidence: 84%

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

Kruse¹,

Pallasch

Bantscheff³

et al. 2010

Leukemia

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The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development.

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Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

Abstract: SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

Cited by 188 publications

References 29 publications

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

The CDK inhibitors in cancer research and therapy

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

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