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Trametinib dimethyl sulfoxide

C 26H

FIN

Mol wt: 693.528

CAS: 1187431-43-1

CAS: 871700-17-3 (free base)

CAS: 871702-06-6 (sodium salt)

CAS: 871702-07-7 (monoacetate salt)

EN: 415494

SUMMARY

Dysregulation of the Ras/Raf/MEK/ERK signaling pathway (also known as the mitogen-activated protein [MAP] kinase pathway) has been implicated in many types of cancer, including melanoma, pan-creas, colon and lung cancer, and this pathway has become an attrac-tive target for therapeutic development. There has been some success in targeting Raf, but previously developed MEK inhibitors have yielded limited clinical benefit. This review focuses on the preclinical and clini-cal development of trametinib dimethyl sulfoxide (GSK-1120212B), a selective MEK 1/2 inhibitor.

Key words: Cancer – MAP kinase kinase inhibitor – Signaling path-way – Trametinib dimethyl sulfoxide – GSK-1120212B SYNTHESIS*

Synthesis of trametinib dimethyl sulfoxide:

Cyclization of 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methyl-amino)uracil (I) (optionally containing some 1-cyclopropyl regioiso-mer) with either diethyl 2-methylmalonate (II) in Ph

O at 220 °C (1) or with 2-methylmalonic acid (III) in Ac

O at 100 °C (2) yields the 5-hydroxypyrido[2,3-d]pyrimidine-2,4,7-trione derivative (IV) (1, 2), which can be separated from its regioisomeric byproduct by crystal-lization from acetone (2). Treatment of compound (IV) with Tf

O in the presence of 2,6-lutidine in CHCl

gives the corresponding triflate (V) (1, 2). Similarly, reaction of (IV) with p-TsCl in the presence of Et

N and Me

N·HCl in acetonitrile produces tosylate (VI) (2). The conden-sation of triflate (V) with 3-nitroaniline (VII) at 130 °C furnishes the 5-(arylamino)pyrido[2,3-d]pyrimidine derivative (VIII), which under-goes rearrangement to the isomeric pyrido[4,3-d]pyrimidine (IX) in the presence of K

in MeOH/THF at 80 °C. Reduction of nitro compound (IX) by means of Na

in DMF/H

O at 90 °C, followed by acetylation of the resulting amine with Ac

O in pyridine/CHCl

, leads to trametinib (X). Finally, crystallization of (X) from DMSO pro-duces trametinib dimethyl sulfoxide solvate (1). Scheme 1.

In an alternative procedure, condensation of either triflate (V) or tosylate (VI) with N-(3-aminophenyl)acetamide (XI) by means of 2,6-lutidine in DMA at 130 °C affords intermediate (XII), which upon rearrangement in the presence of NaOMe in THF/MeOH gives rise to the pyrido[4,3-d]pyrimidine compound (IX) (2). Scheme 1.

Uracil intermediate (I) is obtained as follows. Condensation of 2-flu-oro-4-iodophenyl isocyanate (XIII) with cyclopropylamine (XIV) in

THOMSON REUTERS

Drugs of the Future 2012, 37(12): 847-853

DOI: 10.1358/dof.2012.37.12.1879452

D.P. Cosgrove. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. E-mail: dcosgro2@https://www.wendangku.net/doc/fb10262296.html,.

*Synthesis prepared by J. Bolòs, R. Casta?er. Thomson Reuters, Proven?a 398, 08025 Barcelona, Spain.MONOGRAPH

TRAMETINIB DIMETHYL SULFOXIDE

USAN MAP Kinase Kinase 1 and 2 (MEK 1/2) Inhibitor

Oncolytic GSK-1120212B

JTP-74057

N-[3-[3-Cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,6,7-hexahydropyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide dimethyl sulfoxide solvate

InChI: 1S/C26H23FIN5O4.C2H6OS/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34;1-4(2)3/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34);1-2H3

TRAMETINIB DIMETHYL SULFOXIDE D.P. Cosgrove

Et 2O (1), or alternatively reaction of 2-fluoro-4-iodoaniline (XV) with

CDI in the presence of Et 3N in DMF, followed by condensation with

cyclopropylamine (XIV) (2) affords disubstituted urea (XVI). Cycliza-

tion of urea (XVI) is treated with malonic acid (XVII) in the presence

of AcCl in Ac 2O at 60 °C affords the pyrimidine trione (XVIII), which

is chlorinated using POCl 3in the presence of PhNMe 2and a catalytic

amount of H 2O at 90 °C to provide a mixture of 6-chloropyrimidine

(XIX) and the corresponding regioisomer. Finally, chloropyrimidine (XIX)

is treated with methylamine (XX) in EtOH at 80 °C (1, 2). Scheme 2.

In an alternative procedure, acylation of urea (XVI) with cyanoacetic

acid (XXI) by means of MsCl in DMF yields the N -(cyanoacetyl)urea

(XXII), which cyclizes in aqueous NaOH at 80 °C to yield the amino-D.P. Cosgrove TRAMETINIB DIMETHYL SULFOXIDE pyrimidine derivative (XXIII). Condensation of amine (XXIII) with dimethylformamide dimethylacetal (XXIV) in DMF affords formami-dine (XXV), which is finally reduced using NaBH 4in EtOH/t -BuOH (2). Scheme 2.BACKGROUND Ras/Raf/MEK/ERK signaling is integral to the transmission from cell surface growth factor receptors, such as epidermal growth fac-tor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-I receptor), to downstream regulators of a variety of cellular processes,including proliferation, growth and apoptosis. As outlined in Figure 1,Raf phosphorylates mitogen-activated protein kinase kinase (MEK) 1

and 2, which then activate extracellular signal-regulated kinase (ERK)-1 and -2 via phosphorylation. Under normal physiological conditions, this pathway is activated by ligand binding to cell surface receptors and tightly regulated to control its output. However, a mutation in one of the members of the signaling cascade (most commonly KRAS and BRAF) will result in constitutive activation of the pathway, in the absence of ligand binding, as is the case in a number of malignancies (3). In such a situation, ERK plays a key role in cellular proliferation by phosphorylation of various transcription factors, and increased levels of phospho-ERK have been described in many cancer types. Both Raf and ERK have multiple downstream targets, but MEK specifically targets ERK, making it a point of con-vergence for the pathway and a rational therapeutic target. There is also ample evidence of cross signaling between the mitogen-acti-vated protein kinase (MAPK) pathway and other intracellular path-ways, including PI3K/Akt/mTOR (4), so adequately inhibiting MEK and associated proteins may impact cancers other than those dependent upon activating mutations within Ras/Raf/MEK/ERK. PRECLINICAL PHARMACOLOGY

Trametinib dimethyl sulfoxide (GSK-1120212B) is a potent, reversible, highly selective, allosteric inhibitor of MEK 1 and MEK 2. The com-pound is noncompetitive towards ATP, and its mechanism of action is considered to be twofold: it inhibits the activation of MEK by Raf kinases, as well as acting as a direct inhibitor of MEK kinases, both MEK 1 and MEK 2. As noted above, oncogenic mutations in both KRAS and BRAF signal occur through MEK 1 and MEK 2. Tumors har-boring such mutations and their resulting increased levels of phos-pho-ERK tend to be more sensitive to inhibition with trametinib dimethyl sulfoxide (5). Yamaguchi and colleagues demonstrated the specificity of the compound for MEK 1 and MEK 2, with no significant activity against a panel of 183 kinases, including MEK 5, the closest kinase homolog to the target kinases (6). Data for the human colon adenocarcinoma HT-29 and the human renal adenocarcinoma ACHN cell lines suggest equal potency against MEK 1 and MEK 2 phosphorylation of ERK. It became evident in multiple cell line stud-ies that the sensitivity to G SK-1120212B was highest in those cells harboring activating mutations in BRAF or KRAS–those with the BRAF V600E mutation were the most sensitive and exhibited a cytotox-ic response in the majority of experiments (7). In these cell lines, G

cell cycle arrest was noted to be fully reversible once trame-tinib dimethyl sulfoxide was removed, suggesting that continuous exposure was necessary to maintain efficacy.

These data were recapitulated in tumor xenograft models, with anti-tumor activity again most pronounced in those models with activat-ing mutations in BRAF and KRAS(human adenocarcinoma COLO 205, malignant melanoma A-375 and HT-29).

TRAMETINIB DIMETHYL SULFOXIDE D.P. Cosgrove

Figure 1.Scheme of mitogen-activated protein kinase (MAPK) pathway, highlighting signal transduction through Ras/Raf/MEK/ERK and crosstalk with the associated PI3K/Akt/mTOR pathway. Trametinib dimethyl sulfoxide inhibits Raf-dependent MEK phosphorylation, as well as MAP kinase kinase 1 and 2 (MEK 1/2) activity, leading to decreased ERK phosphorylation and cellular proliferation.

Confirmation of target inhibition was carried out in a subset of patients with melanoma harboring mutations in BRAF or KRAS. At the recommended dose of 2 mg trametinib dimethyl sulfoxide once a day, there was a 62% inhibition of phospho-ERK, an 83% inhibition of antigen KI-67 and a 175% increase in p27 in the tumor tissue, indi-cating the potential development of predictive molecular biomark-ers for this compound. Indeed, GlaxoSmithKline carried out a com-prehensive predictive biomarker analysis for trametinib dimethyl sulfoxide, using almost 300 solid tumor and hematological malig-nancy cell lines, and identified a variety of additional markers of response in tumors with existing BRAF/KRAS mutations, as well as markers of increasing sensitivity despite the absence of such muta-tions (7). This highlights the complexity of interactions involving the MAPK pathway, and MEK as a central mediator of signaling. PHARMACOKINETICS AND METABOLISM

Trametinib dimethyl sulfoxide is orally bioavailable. It is rapidly

absorbed, with a median t

max occurring within 1-3 hours of adminis-

tration. It accumulates with repeat dosing, has a long elimination phase and an effective half-life of 4-5 days. At and around the rec-

ommended dosing schedule of 2 mg daily, AUC and C

max values are

dose-proportional. The compound has a shallow C

max to C

trough

phar-

macokinetic profile, which, in conjunction with the long half-life, makes for an easily achievable, prolonged steady-state drug concen-tration. In an initial clinical trial, mean plasma concentrations of trametinib dimethyl sulfoxide were greater than the preclinical tar-get concentration throughout the dosing interval (8). This is ideal for inhibition of tumors with activating mutations in the MAPK pathway, even at the convenient once-daily dosing regimen. There are no available data on protein binding, and distribution data are limited to mouse studies which revealed no penetration into brain tissue. Trametinib dimethyl sulfoxide is hepatically cleared, with oxidation by cytochrome P450 CYP3A4, and deacetylation, glucuronidation and monooxygenation via hepatic microsomes.

SAFETY

As noted below, the first-in-human trial of trametinib dimethyl sul-foxide identified a maximum tolerated dose (MTD) of 3 mg/day and a suggested monotherapy dose of 2 mg/day (8). This apparent dis-crepancy arose because of concerns about the long-term tolerabili-ty of the 3 mg/day dose. While it was identified as the MTD during cycle 1 of treatment, a number of subjects experienced dose-limiting toxicities in subsequent cycles, and so the 2 mg/day dose was rec-ommended for future trials. At higher doses, a larger number of trial patients were noted to have grade 2 rash, any grade rash leading to dose reduction, peripheral edema and cardiac failure. At the recom-mended dose, the most common adverse events (AEs) included diarrhea (42%), acneiform rash (80%), nausea, vomiting, anorexia, fatigue, peripheral edema, pruritus, elevated AST/ALT, fever, consti-pation, anemia and febrile neutropenia. There were very few grade 3 AEs, < 5%. A rare but serious AE noted in two patients was central serous retinopathy (CSR), occurring a few weeks after starting drug and resolving spontaneously. Both patients successfully restarted trametinib dimethyl sulfoxide at lower doses after resolution, but baseline ophthalmological exam is now recommended prior to administration. There did not appear to be any correlation between toxicity and efficacy of the drug.CLINICAL STUDIES

The first-in-human study of trametinib dimethyl sulfoxide was car-ried out at 12 centers in the U.S. between 2008 and 2011 (8). Known as MEK111054 (NCT00687622), the trial sought to identify the MTD in patients with advanced solid tumors, as well as to clarify the phar-macokinetics, pharmacodynamics and clinical response with this agent. A total of 206 patients were enrolled in the trial and the MTD was established at 3 mg/day. Target inhibition was assessed by measuring the percent reduction in phospho-ERK after treatment. This reduction was more marked in patients with tumors that har-bored activating mutations in BRAF and KRAS, hinting at more spe-cific targeting to specific tumor types. Indeed, of the clinical responses seen in this phase I study, the majority were in BRAF-mutant melanoma patients (17 objective responses, 14 confirmed). Responses were also noted in patients with pancreas cancer (2), and KRAS-mutant non-small cell lung cancer (NSCLC) (9), for a total of 21 objective responses, with 18 confirmed. Common AEs seen in those groups treated at or near the MTD included rash, diarrhea, fatigue, nausea, vomiting and peripheral edema. Only four deaths occurred in this study, including one pulmonary embolism, one intracranial bleed, one renal failure and one sudden death.

The sponsor conducted an expansion cohort of the original MEK111054 study, involving 25 patients with metastatic NSCLC, treated at the recommended dose of 2 mg/day. This group was enriched for those with mutated KRAS(16 patients), and early effica-cy results for these patients revealed 2 confirmed partial responses, 2 minor responses and 2 with stable disease, and a preliminary median progression-free survival (PFS) of 3.8 months in this heavily pretreated population. In contrast, no objective responses were noted in those patients with wild-type KRAS within this expansion. These data have not yet been published.

Overall, this initial study suggested that trametinib dimethyl sulfox-ide was a relatively safe and well tolerated agent, and there was an initial efficacy signal, especially in tumors harboring activating mutations in the MAPK pathway. The MTD was 3 mg/day, and the recommended phase II dose for monotherapy was 2 mg/day based on the safety profile, pharmacokinetics, pharmacodynamics and effi-cacy.

Since a majority of melanomas have activating mutations in BRAF, this was felt to be a fertile clinical area in which to develop trame-tinib dimethyl sulfoxide. Indeed, active BRAF requires MEK to ampli-fy its signal, so these particular tumors should be dependent on MEK and exquisitely sensitive to an effective MEK inhibitor. With this infor-mation, and given the success of targeting mutant BRAF V600E melanoma with Raf-targeted monotherapy (9), the MEK111054 investigators analyzed the cohort of melanoma patients within their phase I study. A total of 97 melanoma patients had been enrolled in this study, 16 with uveal melanoma and 81 with cutaneous or unknown primary melanoma (10). In contrast with prior studies of BRAF inhibitors (9), there were no cutaneous squamous cell carcino-mas (SCCs) identified during this trial. The majority of patients had available tumor samples for BRAF mutational analysis, with 36 con-firmed mutant BRAF and 39 confirmed wild-type BRAF. Most patients with a BRAF mutation had not received a prior B-raf inhibitor, and this group had a confirmed RECIST response rate of 33% and a median PFS of 5.7 months (95% confidence interval [CI]: 4.0-7.2 months). Those patients with wild-type BRAF tumors had a

D.P. Cosgrove TRAMETINIB DIMETHYL SULFOXIDE

confirmed response rate of only 10%, all partial responses, in keep-ing with the preclinical findings of enhanced sensitivity to trametinib dimethyl sulfoxide in cells with a constitutively active MAPK path-way.

Building on this promising data, a large, open-label phase III trial was carried out in patients with BRAF mutant melanoma (either V600E or V600K mutations), assessing trametinib dimethyl sulfox-ide against cytotoxic chemotherapy (11; NCT01245062). A total of 322 patients were assigned to trametinib dimethyl sulfoxide 2 mg once daily or intravenous dacarbazine or paclitaxel at standard doses once every 3 weeks. Crossover to the trametinib dimethyl sul-foxide arm was permitted if disease progression was noted on either chemotherapeutic agent. Median PFS was 4.8 months in the tram-etinib dimethyl sulfoxide group and 1.5 months in the chemotherapy group (hazard ratio [HR] for trametinib dimethyl sulfoxide: 0.45; 95% CI: 0.33-0.63; P< 0.001), thus meeting the study’s primary endpoint. Despite the permitted crossover, there was even a positive overall survival (OS) signal from this study, with 6-month OS of 81% in the trametinib dimethyl sulfoxide group and 67% in the chemotherapy group (HR for trametinib dimethyl sulfoxide: 0.54; 95% CI: 0.32-0.92; P= 0.01). The toxicity profile in this larger study mirrored that of the earlier trial, with acneiform rash, diarrhea and peripheral edema proving most common but generally mild. Howev-er, in this trial, 7% of patients receiving trametinib dimethyl sulfoxide experienced a decreased ejection fraction or ventricular dysfunction, including two patients with grade 3 cardiac events that led to per-manent discontinuation of study drug. Once again, no secondary cutaneous SCCs were reported. Overall, dose adjustments and inter-ruptions were required in about one-third of the patients in the trametinib dimethyl sulfoxide group.

These results were comparable to those seen with the BRAF inhibitor vemurafenib in a similar trial design and treatment popula-tion (9). Trametinib dimethyl sulfoxide and vemurafenib provide equivalent improvements in PFS and OS when compared to chemotherapy. Vemurafenib appeared to elicit a better objective response rate (ORR; 44%) than trametinib dimethyl sulfoxide (22%), but also generated a significant number of cutaneous SCCs and a slightly different toxicity profile.

The relatively low ORR seen with trametinib dimethyl sulfoxide in this susceptible population with BRAF mutated melanoma high-lights the need for further investigation into how a constitutively active MAPK pathway integrates with other intracellular pathways to contribute to tumor cell viability (12). While appropriate targeting of this pathway has a discernible impact on the ability of tumor cells to grow and proliferate, it is unlikely that trametinib dimethyl sulfoxide monotherapy (or monotherapy with any small-molecule signaling inhibitor) will lead to prolonged eradication of tumors in the majori-ty of patients.

To this end, trametinib dimethyl sulfoxide is currently under investi-gation in numerous combination clinical trials, with both other tar-geted agents and traditional cytotoxic chemotherapeutic agents. Flaherty et al. have recently published results from a phase I/II trial assessing the combination of trametinib dimethyl sulfoxide and dabrafenib (another BRAF inhibitor), carried out to assess whether resistance to BRAF inhibition in patients with BRAF V600mutant melanoma can be mitigated by more complete targeting of the MAPK pathway with the addition of the MEK inhibitor (13; NCT01072175). The study design was rather complex, but in essence, 85 patients were enrolled in the phase I portion (which included both melanoma and colorectal cancer patients with BRAF V600muta-tions), and the agents were safely combined at full monotherapy doses (2 mg/day trametinib dimethyl sulfoxide, 150 mg b.i.d. dabrafenib). One hundred and sixty-two patients were then enrolled in the phase II portion, all with BRAF V600mutant melanoma, and assigned to dabrafenib monotherapy or dabrafenib in combination with either 1 or 2 mg/day trametinib dimethyl sulfoxide. Primary endpoints included the incidence of cutaneous SCCs and PFS. Patients receiving monotherapy exhibited a 19% incidence of cuta-neous SCCs, while patients receiving combination therapy had only a 7% incidence, although this difference did not meet statistical sig-nificance (P= 0.09). Median PFS was 5.8 months in the monother-apy group and 9.4 months in the combination therapy group (HR for the combination: 0.55; 95% CI: 0.33-0.93; P= 0.02). These results highlight the potential for overcoming at least some of the resist-ance mechanisms that arise in tumors after inhibition of a specific kinase by rational combinatorial therapies, and a number of phase III trials of B-raf and MEK inhibitor combinations are ongoing in both the metastatic and adjuvant settings.

GSK has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for trametinib dimethyl sulfoxide for the treatment of BRAF V600mutant melanoma based upon the results of the above trials.

DRUG INTERACTIONS

Although the available data are limited, trametinib dimethyl sulfox-ide has a relatively low C

max

at the recommended treatment dose, and is considered unlikely to have clinically significant drug interac-tions. There is preclinical evidence of potential CYP450 enzyme interactions, with mild induction of CYP3A4 and mild inhibition of CYP2C8 at moderate concentrations. Based on this, the pharmaco-kinetics of CYP2C8-metabolized drugs could be perturbed by coad-ministration with trametinib dimethyl sulfoxide. Specifically, impaired elimination of these drugs could be expected. The most important within this group may be the insulin-sensitizing thiazol-idinediones, such as pioglitazone. In contrast, the systemic exposure of trametinib dimethyl sulfoxide may be increased or decreased by coadministration with CYP3A4 inhibitors or inducers, respectively. CYP3A4 inhibitors that may increase trametinib dimethyl sulfoxide exposure include the azole antifungal agents, protease inhibitors (nelfinavir, ritonavir), calcium channel blockers (diltiazem, vera-pamil) and macrolide antibiotics (erythromycin). CYP3A4 inducers to consider include anticonvulsants (phenytoin, carbamazepine) and reverse transcriptase inhibitors (efavirenz, nevirapine). No clinical data are yet available to estimate the extent of these potential inter-actions.

FUTURE DIRECTIONS

In addition to maximizing the potential of trametinib dimethyl sul-foxide in the abrogation of MAPK signaling, at least three studies are ongoing assessing the agent with inhibitors of the PI3K/Akt/mTOR pathway based on the preclinical findings of significant crosstalk between this and the MAPK pathway, as noted above (4). A number

TRAMETINIB DIMETHYL SULFOXIDE D.P. Cosgrove

of other targeted agents are being looked at in combination with trametinib dimethyl sulfoxide in rationally designed trials focusing on the molecular assessment of tumor and posttreatment assess-ment of target inhibition, which, for the moment, still requires direct sampling of tumor tissue. While these studies do limit potential par-ticipants, the information generated should inform translational questions moving forward. Studies utilizing trametinib dimethyl sul-foxide in combination with cytotoxic agents are enriched for patients more likely to have constitutively active MAPK, including pancreatic cancer and KRAS/NRAS mutant NSCLC, among others.

The results of these trials are awaited with interest, and the recently published predictive biomarker analysis for the compound (7) should lead to new avenues of clinical research beyond those tumors dependent on mutations in KRAS and BRAF for their proliferative potential. It is likely that a large number of tumors will rely on sig-naling through MEK for growth, proliferation and avoidance of apop-tosis, and, as evidenced by the aforementioned data in melanoma, focused inhibition of MEK will impact these processes. In the B-raf/ MEK combination studies, the addition of trametinib dimethyl sul-foxide overcame one of the major resistance mechanisms to B-raf inhibition, i.e., enhanced MAPK signaling (13). However, these stud-ies also confirmed that resistance mechanisms to this agent remain to be elucidated, with preclinical data suggesting this resistance is likely mediated both through reactivation of this same MAPK path-way, as well as MAPK-independent compensatory signaling. While much work lies ahead, it is hoped, given the integral role MEK plays in downstream signaling and crosstalk, that trametinib dimethyl sul-foxide, with its ideal mechanistic, pharmacokinetic and toxicity attributes, can help to maximize the promise of a personalized approach to cancer therapy in the future.

SOURCES

Japan Tobacco, Inc. (JP); licensed to GlaxoSmithKline (UK).

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D.P. Cosgrove TRAMETINIB DIMETHYL SULFOXIDE