Cell lines

WT (YUVON and YUROB), B-RAF mutant (YUKSI and YUMAC) and N-RAS mutant (YUDOSO and YUKIM) cells

Preparation method

The solubility of this compound in DMSO is >22.1mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

10-1000 nM; 4 and 24 hours

Applications

Compared to sensitive cultures (YUROB, YUMAC, YUDOSO, YUKIM), in the MEK162 resistant melanoma cultures (YUVON and YUKSI), the baseline level of phospho-ERK1/2 and the ratio of phospho-ERK1/2 to total ERK1/2 was lower. In MEK162-sensitive melanomas, MEK162 significantly decreased the level of ERK1/2 phosphorylation and clonogenic survival, and induced apoptosis.

Animal models

Rat collagen-induced arthritis (CIA) and rat adjuvant-induced arthritis (AIA) models

Dosage form

CIA studies: 0.3, 1 or 3 mg/kg ARRY-438162 (PO, BID) with or without 30 mg/kg ibuprofen (PO, QD) for six days.AIA model: 1, 3 or 10 mg/kg ARRY-438162 (PO, QD) beginning on day 8 and continuing for 6 days, with or without the addition of 0.05 mg/kg methotrexate (PO, QD) which was dosed days 0-13.

Application

In rat collagen-induced arthritis (CIA) model, ARRY-438162 inhibited increases in ankle diameter by 27% and 50% at 1 and 3 mg/kg, while ibuprofen had 46% inhibition. When combined with ibuprofen, these same two doses resulted in 74% and 72% inhibition, respectively and also inhibited joint destruction by 54% and 77%, respectively. In AIA model, when combined with MTX, 3 and 10 mg/kg of ARRY-438162 inhibited ankle diameter by 55% and 71%, respectively.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

MEK162 (ARRY-162, ARRY-438162) is a novel, selective inhibitor of MEK 1/2 with IC50 of about 12 nM [1].

Co-treatment of MEK162 and PKC inhibitors persistently inhibited MAP-kinase pathway. The co-treatment can halt proliferation and induce apoptosis of uveal melanoma cells even with GNAQ or GNA11 mutations [2]. All N-RAS mutant melanoma cells were sensitive to MEK 162. MEK162 reduced ERK1/2 phosphorylation, clonogenic survival, and induced apoptosis [3].

Phase Ib or II clinical trials were conducted in 32 cutaneous melanoma patients. 20 patients in MEK162 monotherapy and 12 on MEK162 plus RAF inhibitor or selective BRAF inhibitor combination therapy underwent ophthalmological examinations and multimodal imaging. These therapy all induced transient retinopathy with multiple bilateral lesions in some patients. The effect of MEK162 in retinopathy has been usually mild, self-limiting, and tolerable [4].

References:
[1]. Jed Pheneger, Eli Wallace, Allison Marlow, Brian Hurley, Joe Lyssikatos, Alison M. Bendele, Patrice A. Lee1. Array BioPharma, Boulder, CO; Bolder BioPath, Boulder, CO. Characterization of ARRY-438162, a potent MEK inhibitor in combination with Methotrexate or Ibuprofen in vivo models of arthritis. American college of rheumatology. 2006 Annual Scientific Meeting.
[2]. Chen X, Wu Q, Tan L, Porter D, Jager MJ, Emery C, Bastian BC. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene. 2013 Oct 21.
[3]. Thumar J, Shahbazian D, Aziz SA, Jilaveanu LB, Kluger HM. MEK targeting in N-RAS mutated metastatic melanoma. Mol Cancer. 2014 Mar 4;13:45.
[4]. Urner-Bloch U, Urner M, Stieger P, Galliker N, Winterton N, Zubel A, Moutouh-de Parseval L, Dummer R, Goldinger SM. Transient MEK inhibitor-associated retinopathy in metastatic melanoma. Ann Oncol. 2014 May 26. pii: mdu169.