Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts.

Sánchez-Martínez, Concepción; Gelbert, Lawrence M.; Shannon, Harlan E.; Dios, Alfonso De; Staton, Brian A.; Ajamie, Rose T.; Wishart, Graham N.; Raub, Thomas J.

doi:10.1158/1535-7163.targ-11-b234

Cited by 28 publications

(18 citation statements)

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“…This is another orally bioavailable drug that selectively inhibits CDK4/6 in the nanomolar range (27). Preclinical data show antitumor activity in a number of models, and the drug has also been shown to cross the blood-brain barrier (28). Preliminary results for 75 patients treated on the phase I study of LY2835219 have been reported (29).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

Dickson

2014

Clinical Cancer Research

214

179

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Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G 1 -S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. Clin Cancer Res; 20(13); 3379-83. Ó2014 AACR.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

Dickson

2014

Clinical Cancer Research

214

179

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“…Abemaciclib formerly LY2835219 (Eli Lilly), like palbociclib and LEE011 is a small molecule selectively targeting CDK4/CDK6 and is orally available. Preclinical data for abemaciclib show antitumor activity in a number of models, and the drug has also been shown to cross the blood–brain barrier (Sanchez-Martinez et al, 2011 ). There are 10 ongoing clinical trials using abemaciclib as a single agent or in combination for the treatment of solid tumors, such as breast and lung cancer; as well as for lymphoma and MCL (Supplementary Table 3; clinicaltrials.gov, accessed 11/2014).…”

Section: Cdk4/cdk6 Inhibitorsmentioning

confidence: 99%

Targeting cell cycle regulators in hematologic malignancies

Aleem

Arceci

2015

Front. Cell Dev. Biol.

104

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Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

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“…All these compounds show good selectivity for CDK4 in preclinical studies (Table 1; refs. [80][81][82][83].…”

Section: Clinical Development Of Cdk4 Inhibitors and Opportunities Fomentioning

confidence: 99%

The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma

Sheppard

McArthur

2013

Clinical Cancer Research

217

170

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The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G 1 -S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16 INK4A ) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become "addicted" to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma.

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Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts.

Cited by 28 publications

References 0 publications

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

Targeting cell cycle regulators in hematologic malignancies

The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma

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