Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

Rana, Sandeep; Sonawane, Yogesh A.; Taylor, Margaret; Kizhake, Smitha; Zahid, Muhammad; Natarajan, Amarnath

doi:10.1016/j.bmcl.2018.10.020

Cited by 19 publications

(17 citation statements)

References 35 publications

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“…ABT-263; ABT-737; 4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)- N -({3-nitro-4-[(tetrahydro-2 H -pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-(2,6-dichlorobenzamido)- N -(piperidin-4-yl)-1 H -pyrazole-3-carboxamide; 5-[3-[4-(aminomethyl)phenoxy]propyl]-2-[(8 E )-8-(1,3-benzothiazol-2-ylhydrazinylidene)-6,7-dihydro-5 H -naphthalen-2-yl]-1,3-thiazole-4-carboxylic acid (WEHI-539); and 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8 H )-one (palbociclib) were purchased from Selleckchem. Results on analog 24 were reported previously by our laboratory (Rana et al, 2018). Antibodies P-RB S807/811 (9308), RB (9309), tubulin (3873), Bcl-xL (2762), Mcl-1 (5453), poly ADP ribose polymerase [(PARP) 9542], Cl.…”

Section: Methodssupporting

confidence: 82%

“…We, and others, have previously reported aminopyrazoles as CDK inhibitors with antitumor activities (Pevarello et al, 2004; Rana et al, 2018). A systematic structure-activity relationship study identified analog 24 as a potent CDK inhibitor (Rana et al, 2018). Cell-free kinase assays show that analog 24 is a CDK2/5 inhibitor (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…CDK5 has been validated as a target in pancreatic cancer (Feldmann et al, 2010); however, the exact mechanism of how CDK5 could promote tumorigenesis is yet to be fully elucidated. Recently, we identified an aminopyrazole-based analog 24 that inhibited CDK2 and CDK5 with nanomolar potency (Rana et al, 2018). Here, we show that analog 24 is a selective CDK5 inhibitor with an IC 50 value of ∼1.1 μ M in MIA PaCa-2 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Using CP-668863 as a guide, we synthesized a focused library of aminopyrazole analogs and identified a potent CDK2/5 inhibitor, 2-([1,1′-biphenyl]-4-yl)- N -(5-cyclobutyl-1 H -pyrazol-3-yl)acetamide (analog 24 ). We found that on an average (in five pancreatic cancer cell lines) analog 24 was ∼2-fold more potent than AT7519 [4-(2,6-dichlorobenzamido)- N -(piperidin-4-yl)-1 H -pyrazole-3-carboxamide] and ∼45-fold more potent than roscovitine [(2R)-2-[[6-(benzylamino)-9-propan-2-ylpurin-2-yl]amino]butan-1-ol] (Rana et al, 2018). Here, we show that analog 24 selectively inhibits the kinase activity of CDK5 over CDK2 in cancer cells and results in reduced Mcl-1 levels.…”

Section: Introductionmentioning

confidence: 99%

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CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax

et al. 2019

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Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,19-biphenyl]-4-yl)-N-(5cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8H)-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 when combined with Bcl2 inhibitor results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 inhibitors. SIGNIFICANCE STATEMENT Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax.

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Section: Methodssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax

et al. 2019

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“…One study has identified mitogen-activated protein kinases (MAPK) and cdc2-related kinases (CRK) to be potential target proteins of a diaminopyrimidine in Trypanosoma brucei and Leishmania major ( 32 ). Other distant analogues have been used in oncology and shown to inhibit human cyclin-dependent kinases (CDK) ( 33 – 35 ) and posttranslational modification processes ( 36 ). In Plasmodium falciparum , mutations in a P-type ATPase were shown to confer resistance to GNF-Pf4492, a pyrazole urea ( 37 ).…”

Section: Introductionmentioning

confidence: 99%

Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance

Kerkhof

Mabille

Hendrickx

et al. 2020

Antimicrob Agents Chemother

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Introduction: Current antileishmanial treatment is hampered by limitations such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles - a highly promising antileishmanial chemical series. Multiple experiments have been performed to anticipate the propensity for resistance development. Methodology: Resistance selection was performed by successive exposure of Leishmania infantum promastigotes (in vitro) and intracellular amastigotes (both in vitro and in golden Syrian hamsters). The stability of resistant phenotypes was assessed after passage in mice and Lutzomyia longipalpis sand flies. Whole genome sequencing (WGS) was performed to identify mutated genes, copy number variations (CNVs) and somy changes. The potential role of efflux pumps (MDR/MRP) in the development of resistance was assessed by co-incubation of aminopyrazoles with specific efflux pump inhibitors (verapamil, cyclosporine A and probenecid). Results: Repeated drug exposure of amastigotes did not result in the emergence of drug resistance, either in vitro or in vivo. Selection on the promastigote stage, however, was able to select for parasites with reduced susceptibility (resistance index: 5-24). This phenotype proved to be unstable after in vivo passage in mice and sand flies, suggesting that non-fixed alterations are responsible for the elevated resistance. In line with this, single nucleotide polymorphisms and indels identified by whole genome sequencing could not be directly linked to the decreased drug susceptibility. Copy number variations were absent, whereas somy changes were detected, which may account for the transient acquisition of resistance. Finally, aminopyrazole activity was not influenced by the MDR and MRP efflux pump inhibitors tested. Conclusion: The selection performed does not suggest rapid development of resistance against aminopyrazoles in the field. Karyotype changes may confer elevated levels of resistance, but these do not seem to be stable in the vertebrate and invertebrate hosts. MDR/MRP efflux pumps are not likely to significantly impact the activity of the aminopyrazole leads.

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Identification of key transcription factors in endometrial cancer by systems bioinformatics analysis

Song

Chen

2019

J of Cellular Biochemistry

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Endometrial cancer (EC) is one of the most common malignant diseases worldwide. Although many studies have been performed on EC, a systems analysis between transcription factors (TFs) and EC relationship remains poorly characterized. Here, we present a systems bioinformatics analysis of TFs in EC patient samples to identify key TFs in EC. First, dysregulated and survival‐related TFs were identified in EC using data from The Cancer Genome Atlas database and Gene Expression Omnibus. Second, we investigated the mechanisms of dysregulated TFs and tested whether their expression is correlated with prognosis of EC. Finally, we addressed new perspectives in EC biomarker research, including comprehensive knowledge of previously suggested candidate biomarkers in conjunction with novel mass spectrometry‐based proteomic technologies with enhanced sensitivity and specificity not yet applied to EC studies, enabling a directed clinical perspective of the study design. Our study identified three promising TFs, E2F1, HMGA1, and PGR, which closely correlate with EC. Although treatments targeting TFs are not always efficient, these TFs may be useful as biomarkers for the diagnosis and prognosis of EC. Furthermore, we found that these dysregulated TFs and their target genes are primarily involved in the cell cycle and may promote endometrial carcinoma occurrence and development. Using integrated bioinformatic analysis, we identified candidate genes and pathways in EC, which could improve our understanding of the etiology and underlying molecular events of EC. Furthermore, these candidate genes and pathways could be therapeutic targets for EC.

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Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

Cited by 19 publications

References 35 publications

CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax

CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax

Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance

Identification of key transcription factors in endometrial cancer by systems bioinformatics analysis

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