A phase I study of selective cyclin dependent kinase inhibitor P1446A-05 administered on an intermittent schedule in patients with advanced refractory tumors.

Gupta, Sudeep; Jain, Minish; Maru, Anish; Nag, Shona; Somani, Naresh; Mehta, Ajay; Kulkarni, Sujay; Acharya, Shivani Anil; Dhobe, Poornima; Jadhav, Nitin

doi:10.1200/jco.2012.30.15_suppl.3011

Cited by 8 publications

(8 citation statements)

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“…P1446A inhibits CDK1, 2, 4, 5, 6, 8 and 9 with IC 50 values of at 25, 180, 90, 210, 210, 12 and 22 nmol/L, respectively (S1 Fig) . P1446A induced cell cycle arrest and apoptosis of solid tumor cell lines in vitro and restricted growth in human colon (HCT-116) and non-small cell lung (H-460) carcinoma xenograft mouse models (Piramal Healthcare Ltd., proprietary information; [24]). Furthermore, P1446A showed promising activity in two independent Phase I clinical trials in patients with solid tumors [25,26]. Here we demonstrate that P1446A inhibits CDK activity and induces rapid apoptosis in peripheral blood CLL cells.…”

Section: Introductionmentioning

confidence: 60%

Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Paiva¹,

Godbersen

Spurgeon

et al. 2015

Blood

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Regimented activation of cyclin/CDK complexes is required for orderly cell cycle progression. Targeting this process has been an attractive therapeutic approach in neoplasia due to cell cycle deregulation and excessive proliferation. CDK inhibitors (notably flavopiridol and dinaciclib) have shown remarkable efficacy in CLL, attributed to their effect on CDK7/9 which is accompanied by a disruption of RNA polymerase-mediated transcription and subsequent deregulation of short-lived pro-survival proteins such as MCL1. Recently, endoplasmic reticulum (ER) stress has been implicated in CDK inhibition in CLL. A novel orally active kinase inhibitor P1446A (Piramal Healthcare Ltd) inhibits CDKs at nM concentrations and has demonstrated clinical activity in Phase I studies in solid tumors with minimal hematologic toxicity. Here we conducted a pre-clinical study of P1446A in CLL B-cells. Peripheral blood cells were obtained from patients with CLL and isolated using standard techniques. 83.3±3.3% of CLL cells underwent apoptosis upon 24-hour exposure to 1.5 µM P1446A, irrespective of chromosomal abnormalities [del(17p)/11q] or IGHV mutationalstatus. Apoptosis occurred as early as 4 hours after drug treatment and was accompanied by a dose-dependent inhibition of interphase CDKs (2/4/6) as evidenced by reduced phospho-Rb (T821/ S780). Apoptosis preceded reduction in RNA polymerase phosphorylation and thus occurred before transcriptional CDK7/9 were inhibited. Meanwhile, targeting CDK2 and CDK4/6 using specific inhibitors did not induce cell death in CLL. We supposed that P1446A could lead to ER stress induction in primary CLL cells, culminating in apoptosis. We noted rapid activation of JNK and p38 MAPK in CLL cells treated with P1446A in vitro. Phosphorylation of JNK and p38 MAPK occurred within 2 hours of treatment with P1446A, preceded onset of apoptosis as measured by PARP cleavage, and was followed by induction of activating transcription factors 2 and 3 (downstream targets of JNK/p38MAPK). Pharmacologic inhibitors of JNK/p38 conferred partial protection from P1446A-mediated apoptosis. We sought to identify the upstream regulators of JNK in this setting. Rapid phosphorylation of ASK1 at Thr845, a site required for its kinase activity, occurred in CLL cells treated with P1446A in a time and dose-dependent manner, concurrently with JNK activation. We observed formation of the trimeric complex between ASK1, IRE1, and TRAF2. Genetic knockdown of ASK1 led to a reduction in JNK phosphorylation and a partial rescue from apoptosis. P1446A did not induce unfolded protein response (UPR) beyond ASK1/JNK/p38 activation, consistent with previous reports on its limited functionality in CLL cells. By contrast, we found that treatment with P1446A led to a dramatic induction of NOXA mRNA and protein levels, in a JNK-dependent manner. In summary, we demonstrate that CDK inhibitor P1446A is a potent inducer of apoptosis in primary CLL cells in vitro. P1446A leads to partial activation of ER stress and the UPR in CLL cells manifested by ASK1-dependent signaling, leading to JNK/p38 MAPK activation and up-regulation of NOXA. This study provides rationale for additional investigations of P1446A in CLL. Disclosures Spurgeon: Bristol Meyers Squibb: Research Funding; Acerta Pharma: Research Funding; Gilead sciences: Honoraria, Research Funding; Genentech: Honoraria; Pharmacyclics: Honoraria; Janssen: Research Funding. Srinivasa:Piramal Healthcare: Employment.

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Section: Introductionmentioning

confidence: 60%

Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Paiva¹,

Godbersen

Spurgeon

et al. 2015

Blood

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“…Since target profiling studies revealed CDK9 as a main target of voruciclib, we next assessed the impact of voruciclib on MCL-1 expression in cell-based and xenograft models of DLBCL. To understand whether clinically achievable and tolerated levels of voruciclib repress MCL-1, we used existing pharmacokinetic data from the two completed Phase 1 trials to model expected plasma drug levels achieved upon dosing with a conservative regimen of 250 mg/day voruciclib 26 , 27 . (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Here we demonstrate that the small molecule flavone derivative, voruciclib, a clinical stage CDK inhibitor, targets CDK9 with sub-nanomolar biochemical potency and represses expression of MCL-1 in multiple models of DLBCL. The safety profile and tolerability of voruciclib has been established by two independent Phase 1 clinical trials 26 , 27 . Furthermore, voruciclib is distinguished from other CDK9 inhibitors such as flavopiridol or dinaciclib by its oral bioavailability, making it an exceptionally attractive candidate for clinical development.…”

Section: Introductionmentioning

confidence: 99%

Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition

Dey

Deckwerth

Kerwin

et al. 2017

Sci Rep

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Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.

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“…It was studied in 10 other clinical trials; however, it is currently not under active development. Voruciclib (P1446A‐05, 73 ) is a structural analog of P276‐00 that inhibits CDK9 (IC 50 = 22 nM) and is orally bioavailable 213–216 . It displays potent antiproliferative activity across 30 cancer cell lines, including prostate, colon, and lung cancer cells 215 .…”

Section: Cdk Inhibitors In Clinical and Preclinical Pipelinementioning

confidence: 99%

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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A phase I study of selective cyclin dependent kinase inhibitor P1446A-05 administered on an intermittent schedule in patients with advanced refractory tumors.

Cited by 8 publications

References 0 publications

Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition

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

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