Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing

Brasca, Maria Gabriella; Albanese, Clara; Alzani, Rachele; Amici, Raffaella; Avanzi, Nilla; Ballinari, Dario; Bischoff, James R.; Borghi, Daniela; Casale, Elena; Croci, Valter; Fiorentini, Francesco; Isacchi, Antonella; Mercurio, Ciro; Nesi, Marcella; Orsini, Paolo; Pastori, Wilma; Pesenti, Enrico; Pevarello, Paolo; Roussel, Patrick; Varasi, Mario; Volpi, Daniele; Vulpetti, Anna; Ciomei, Marina

doi:10.1016/j.bmc.2010.01.042

Cited by 62 publications

(44 citation statements)

References 13 publications

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“…(IC 50 , 62 nmol/L), Cdk9 (IC 50 , 138 nmol/L), and glycogen synthase kinase 3β (IC 50 , 79 nmol/L) in biochemical assays while sparing (IC 50 , >10 μmol/L) 35 additional tyrosine and serine-threonine kinases tested (17). Treatment of A2780 tumor cell line with PHA-793887 in vitro was previously shown by Western blot analysis to partially inhibit Rb phosphorylation at 1 μmol/L and almost completely at 3 μmol/L (17).…”

Section: Resultsmentioning

confidence: 99%

“…These doses, when administered daily for 10 days in similar experiments, induced tumor growth inhibition in the range of 50% (15 mg/kg) to 75% (30 mg/kg) versus untreated mice, respectively. In addition, the dose of 30 mg/kg was shown by immunohistochemistry to significantly reduce Rb phosphorylation (17). Compound plasma levels were measured for both doses, showing an area under the curve (AUC) 0-∞ of 16.9 μmol/L·h at 15 mg/kg and of 34.5 μmol/L·h at 30 mg/kg.…”

Section: Resultsmentioning

confidence: 99%

“…In preclinical studies, in vitro and in vivo treatment of the A2780 ovarian carcinoma tumor cell line with PHA-793887 resulted as expected in inhibition of Rb phosphorylation due to Cdk2 and Cdk4 inhibition, which could be followed by Western blot or immunohistochemical analyses using anti-phospho-Rb antibodies (17).…”

Section: Introductionmentioning

confidence: 86%

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Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

Locatelli

Bosotti

Ciomei

et al. 2010

Molecular Cancer Therapeutics

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A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

Locatelli

Bosotti

Ciomei

et al. 2010

Molecular Cancer Therapeutics

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“…Thus CDK4i may cause diabetes, CDK2i sterility, CDK6i anemia and CDK1i, CDK10i or CDK11i mediate a broad cytotoxicity. 8,10,11 A potent multi-targeted CDKi such as PHA-793887, 12 which inhibits CDK1, CDK2 and CDK4, was studied in a context of a Phase I study conducted at two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR) 13 (companion paper). Fifteen patients were treated at IGR.…”

Section: Abstract: Tlr Dendritic Cells Cancer Herpes Cdk Inhibitorsmentioning

confidence: 99%

“…12 The primary objective of this Phase I, open-label, non-randomized, multicenter, doseescalation study was to determine the maximum tolerated dose (MTD) and the associated dose-limiting toxicities (DLTs) during the first cycle of PHA-793887 in patients with advanced/metastatic solid tumors. Patients received repeated cycles of PHA-793887 administered as a 1 hour IV infusion on day 1, 8, 15 of ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Section: Cdk Inhibition Promotes Reactivation Of Herpes Virus Infectimentioning

confidence: 99%

An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpes viridae

Zoubir¹,

Flament²,

Gdoura³

et al. 2011

Cell Cycle

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Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Bhurta

Bharate

2021

Medicinal Research Reviews

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Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin‐dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino‐pyrimidine is a well‐represented scaffold. The three‐nitrogen framework of amino‐pyrimidine is a fundamental hinge‐binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose‐limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP‐binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

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Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing

Cited by 62 publications

References 13 publications

Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpes viridae

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

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