This Article Full Text Full Text (PDF) Supplementary Data, Yeh, et al. Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yeh, T. C. Articles by Wallace, E. Search for Related Content PubMed PubMed Citation Articles by Yeh, T. C. Articles by Wallace, E.

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Authors' Affiliation: Array BioPharma, Inc., Boulder, Colorado

Requests for reprints: Tammie C. Yeh, Cell Biology, Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301. Phone: 303-386-1298; E-mail: Tammie.Yeh{at}arraybiopharma.com.

Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models.

Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models.

Results: The IC₅₀ of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor–induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate–induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday.

Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.

This article has been cited by other articles:

				E. J. Chung, A. P. Brown, H. Asano, M. Mandler, W. E. Burgan, D. Carter, K. Camphausen, and D. Citrin In vitro and In vivo Radiosensitization with AZD6244 (ARRY-142886), an Inhibitor of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase 1/2 Kinase Clin. Cancer Res., May 1, 2009; 15(9): 3050 - 3057. [Abstract] [Full Text] [PDF]

				W. W. Ma and A. A. Adjei Novel Agents on the Horizon for Cancer Therapy CA Cancer J Clin, March 1, 2009; 59(2): 111 - 137. [Abstract] [Full Text] [PDF]

				B. B. Friday, C. Yu, G. K. Dy, P. D. Smith, L. Wang, S. N. Thibodeau, and A. A. Adjei BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins Cancer Res., August 1, 2008; 68(15): 6145 - 6153. [Abstract] [Full Text] [PDF]

				J. L. Marks, Y. Gong, D. Chitale, B. Golas, M. D. McLellan, Y. Kasai, L. Ding, E. R. Mardis, R. K. Wilson, D. Solit, et al. Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma Cancer Res., July 15, 2008; 68(14): 5524 - 5528. [Abstract] [Full Text] [PDF]

				J. S. Sebolt-Leopold Advances in the Development of Cancer Therapeutics Directed against the RAS-Mitogen-Activated Protein Kinase Pathway Clin. Cancer Res., June 15, 2008; 14(12): 3651 - 3656. [Abstract] [Full Text] [PDF]

				A. A. Adjei, R. B. Cohen, W. Franklin, C. Morris, D. Wilson, J. R. Molina, L. J. Hanson, L. Gore, L. Chow, S. Leong, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers J. Clin. Oncol., May 1, 2008; 26(13): 2139 - 2146. [Abstract] [Full Text] [PDF]

				H. Hamed, W. Hawkins, C. Mitchell, D. Gilfor, G. Zhang, X.-Y. Pei, Y. Dai, M. P. Hagan, J. D. Roberts, A. Yacoub, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo Mol. Cancer Ther., March 1, 2008; 7(3): 616 - 629. [Abstract] [Full Text] [PDF]

				B. B. Friday and A. A. Adjei Advances in Targeting the Ras/Raf/MEK/Erk Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer Therapy Clin. Cancer Res., January 15, 2008; 14(2): 342 - 346. [Abstract] [Full Text] [PDF]

				D. W. Ball, N. Jin, D. M. Rosen, A. Dackiw, D. Sidransky, M. Xing, and B. D. Nelkin Selective Growth Inhibition in BRAF Mutant Thyroid Cancer by the Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4712 - 4718. [Abstract] [Full Text] [PDF]

				Y.-T. Tai, M. Fulciniti, T. Hideshima, W. Song, M. Leiba, X.-F. Li, M. Rumizen, P. Burger, A. Morrison, K. Podar, et al. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis Blood, September 1, 2007; 110(5): 1656 - 1663. [Abstract] [Full Text] [PDF]

				B. R. Davies, A. Logie, J. S. McKay, P. Martin, S. Steele, R. Jenkins, M. Cockerill, S. Cartlidge, and P. D. Smith AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models Mol. Cancer Ther., August 1, 2007; 6(8): 2209 - 2219. [Abstract] [Full Text] [PDF]