LY2835219

LY2835219 is a selective and orally available dual cyclin-dependent kinases 4/6 (CDK4/6) inhibitor that potently inhibits the activities of CDK4 and CDK6 with the half maximal inhibition concentration IC50 values of 2 nM and 10 nM respectively [1].

LY2835219 has also been found to inhibit Rb phosphorylation both in vivo and in vitro leading to specific cell arrest at G1 phase as well as the inhibition of tumor growth [1].

Since the blood brain barrier (BBB) is a major obstacle for the effective treatment of primary brain tumors and brain metastases, LY2835219, which is able to cross the BBB, has the potential to inhibit intracranial tumor growth alone or in combination with other agents [1].

References:
[1] Concepcion Sanchez-Martinez, Lawrence M. Gelbert, Harlan Shannon, Alfonso De Dios, Brian A. Staton, Rose T. Ajamie, Geri Sawada, Graham N. Wishart and Thomas J. Raub. 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 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B234.

The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma.[Pubmed:26909611]

Oncotarget. 2016 Mar 22;7(12):14803-13.

Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.

Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.[Pubmed:24919854]

Invest New Drugs. 2014 Oct;32(5):825-37.

The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.

Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo.[Pubmed:27816545]

Biochem Pharmacol. 2017 Jan 15;124:29-42.

Multidrug resistance (MDR) is the major obstacle of the success in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, play a significant role in mediating MDR by pumping anticancer drugs out of cancer cells. Abemaciclib (LY2835219) is an orally bioavailable CDK4/6 inhibitor under phase III clinical trials. Here, we found that LY2835219 remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Furthermore, LY2835219 significantly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, LY2835219 is likely a competitive inhibitor of ABCB1 and ABCG2 for its competition with [125I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, LY2835219 did not alter the expression level of ABCB1 and ABCG2, and the phosphorylation status of retinoblastoma (Rb) pathway in both parental and their resistant cells. In conclusion, these findings revealed a novel role of LY2835219 in reversing ABCB1 or ABCG2-mediated MDR, which may be benefit to the patients with MDR cancer for combinational therapy.

The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation.[Pubmed:25122067]

Mol Cancer Ther. 2014 Oct;13(10):2253-63.

B-RAF selective inhibitors, including vemurafenib, were recently developed as effective therapies for melanoma patients with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance largely due to reactivation of MAPK signaling. Inhibitors of MAPK signaling, including MEK1/2 inhibitor trametinib, failed to show significant clinical benefit in patients with acquired resistance to vemurafenib. Here, we describe that cell lines with acquired resistance to vemurafenib show reactivation of MAPK signaling and upregulation of cyclin D1 and are sensitive to inhibition of LY2835219, a selective inhibitor of cyclin-dependent kinase (CDK) 4/6. LY2835219 was demonstrated to inhibit growth of melanoma A375 tumor xenografts and delay tumor recurrence in combination with vemurafenib. Furthermore, we developed an in vivo vemurafenib-resistant model by continuous administration of vemurafenib in A375 xenografts. Consistently, we found that MAPK is reactivated and cyclin D1 is elevated in vemurafenib-resistant tumors, as well as in the resistant cell lines derived from these tumors. Importantly, LY2835219 exhibited tumor growth regression in a vemurafenib-resistant model. Mechanistic analysis revealed that LY2835219 induced apoptotic cell death in a concentration-dependent manner in vemurafenib-resistant cells whereas it primarily mediated cell-cycle G1 arrest in the parental cells. Similarly, RNAi-mediated knockdown of cyclin D1 induced significantly higher rate of apoptosis in the resistant cells than in parental cells, suggesting that elevated cyclin D1 activity is important for the survival of vemurafenib-resistant cells. Altogether, we propose that targeting cyclin D1-CDK4/6 signaling by LY2835219 is an effective strategy to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAF V600E melanoma.

Abemaciclib methanesulfonate (LY2835219 methanesulfonate) is a selective CDK4/6 inhibitor with IC50s of 2 nM and 10 nM for CDK4 and CDK6, respectively.

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