Tuesday, May 19, 2015

Drugs in Clinical Pipeline: MK-2206

MK-2206 [8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f] [1,6]naphthyridin-3(2H)-one] is an oral, highly selective allosteric inhibitor of AKT (protein kinase B [PKB]). MK-2206 binds at a site in the pleckstrin-homology (PH) domain, distinct from the ATP-binding pocket, resulting in a conformational change that prevents the localization of AKT to the plasma membrane and its subsequent activation. It displays nanomolar (nM) potency against all 3 AKT isoforms (AKT1, IC50 = 5 nM; AKT2, IC50 = 12 nM; AKT3, IC50 = 65 nM) [1,2].

In vitro, MK-2206 demonstrated synergy with both erlotinib and lapatinib in inhibiting proliferation and inducing apoptosis of non-small cell lung (NSCLC) cell lines, including those that were RAS mutant, and breast cancer cell lines. Treatment with erlotinib inhibited EGFR and pERK phosphorylation of the RAF-RAS-MEK pathway in the A431 cell line and mouse NCI-H292 tumor xenografts and the combination with MK-2206 resulted in decreased levels of pAKT and pRAS40. pAKT and pRAS40 levels were not affected by erlotinib singularly. The inhibition of both pathways led to more profound inhibition of pGSK3b and pS6, which are downstream signaling proteins that correlate with cell growth and survival. The combination also demonstrated significantly greater in vivo tumor growth suppression and tumor regressions over each single agent using both a 3 times per week and QW schedule of MK-2206 in the mouse tumor xenografts [3].

In vitro, MK-2206 demonstrated synergy with several conventional cytotoxics, including carboplatin and docetaxel, in inhibiting the growth of NCI-H292 and A2780 tumor cells. Carboplatin-induced apoptosis was also enhanced by MK-2206 in a sequence-dependent manner: concurrent treatment or pretreatment with carboplatin induced A2780 cell death in a dose-dependent manner, whereas pretreatment with MK-2206 did not. In vivo, MK-2206 synergised with docetaxel, carboplatin, and gemcitabine in inhibiting the growth of PC-3 prostate and NCI-H462 tumor xenografts with a similar-sequence dependent pattern as for carboplatin in vitro [3].

The activity of MK-2206 is as follows:

IC50 (AKT1 enzyme assay) = 5 nM
IC50 (AKT2 enzyme assay) = 12 nM
IC50 (AKT2 enzyme assay) = 65 nM

Common Name: MK-2206
Synonyms:  MK-2206; MK2206; MK 2206
IUPAC Name: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f] [1,6]naphthyridin-3(2H)-one
CAS Number: 1032349-93-1; 1032349-77-1 (hydrochloride); 1032350-13-2 (dihydrochloride)
SMILES: C1CC(C1)(C2=CC=C(C=C2)C3=C (C=C4C(=N3)C=CN5C4=NNC5=O) C6=CC=CC=C6)N
Mechanism of Action: Kinase Inhibitor; AKT Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Phase II
Company: Merck

1. Yan, L. A potent allosteric AKT inhibitor. AACR 2009, abstract DDT01-1.
2. Molife, L. R.; et. al. Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol 2014, 7, 1.
3. Hirai, H.; et. al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010, 9(7), 1956-1967.