6‐Substituted Pyrrolo[3,4‐c]pyrazoles: An Improved Class of CDK2 Inhibitors

Brasca, Maria Gabriella; Albanese, Clara; Amici, Raffaella; Ballinari, Dario; Corti, Luca; Croci, Valter; Fancelli, Daniele; Fiorentini, Francesco; Nesi, Marcella; Orsini, Paolo; Orzi, Fabrizio; Pastori, Wilma; Perrone, Ettore; Pesenti, Enrico; Pevarello, Paolo; Riccardi-Sirtori, Federico; Roletto, Fulvia; Roussel, Patrick; Varasi, Mario; Vulpetti, Anna; Mercurio, Ciro

doi:10.1002/cmdc.200600302

Cited by 24 publications

(12 citation statements)

References 24 publications

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“…We previously described optimization of a chemical class of CDK2 inhibitors, the 6-substituted pyrrolo [3,4-c] pyrazoles (25), and identification of a new orally available compound, PHA-848125 (26), which shows crossreactivity toward CDK1, CDK4, CDK5, and CDK7. Differently from the other CDKIs, PHA-848125 is also highly potent toward TRKA and TRKC, supporting a rationale for testing this agent in selected cancer types where the neurotrophin/TRK receptor axis is thought to play a significant role.…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC 50 . PHA-848125-treated cells show cell cycle arrest in G 1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243-54. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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“…The pyrrolo[3,4‐c]pyrazoles have previously been investigated for their CDK2, PAK, and Aurora‐A kinase activities . To make a concise and conclusive result with the previously reported information, the TrkA inhibition study was planned as follows.…”

Section: Methodsmentioning

confidence: 99%

Identification of Pyrrole[3,4‐c]pyrazoles as Potent Tropomyosin Receptor Kinase A (TrkA) Inhibitors

Choe

Son

Byun

et al. 2016

Bulletin Korean Chem Soc

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“…As the esterification of the Boc protected α-Tfm-alanines with benzyl alcohol in various standard conditions did not proceeded cleanly, we decided to take advantage of the high acidity of the fluorinated carboxylic acid to perform the alkylation of the carboxylate formed in mild basic conditions. The benzylic esters (R)-3 and (S)-3 were obtained in good yields by treatment of the Boc protected α-Tfm-alanines with a slight excess of benzyl bromide in the presence of potassium carbonate (Wipf and Heimgartner 1987;Brasca et al 2007;Li et al 2011) (Scheme 1).…”

Section: Boc/benzyl Protectionmentioning

confidence: 99%

Synthesis of protected enantiopure (R) and (S)-α-trifluoromethylalanine containing dipeptide building blocks ready to use for solid phase peptide synthesis

et al. 2016

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Considering the increasing importance of fluorinated peptides, the development of efficient and reliable synthetic methods for the incorporation of unnatural fluorinated amino acids into peptides is a current matter of interest. In this study, we report the convenient Boc/benzyl and Cbz/tert-butyl protection of both enantiomers of the quaternarized amino acid α-trifluoromethylalanine [(R)- and (S)-α-Tfm-Ala]. Because of the deactivation of the nitrogen atom of this synthetic amino acid by the strong electron withdrawing trifluoromethyl group, the peptide coupling on this position is a challenge. In order to provide a robust synthetic methodology for the incorporation of enantiopure (R)- and (S)-α-trifluoromethylalanines into peptides, we report herein the preparation of dipeptides ready to use for solid phase peptide synthesis. The difficult peptide coupling on the nitrogen atom of the α-trifluoromethylalanines was performed in solution phase by means of highly electrophilic amino acid chlorides or mixed anhydrides. The synthetic effectiveness of this fluorinated dipeptide building block strategy is illustrated by the solid phase peptide synthesis (SPPS) of the Ac-Ala-Phe-(R)-α-Tfm-Ala-Ala-NH2 tetrapeptide.

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6‐Substituted Pyrrolo[3,4‐c]pyrazoles: An Improved Class of CDK2 Inhibitors

Cited by 24 publications

References 24 publications

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Identification of Pyrrole[3,4‐c]pyrazoles as Potent Tropomyosin Receptor Kinase A (TrkA) Inhibitors

Synthesis of protected enantiopure (R) and (S)-α-trifluoromethylalanine containing dipeptide building blocks ready to use for solid phase peptide synthesis

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