Transgenic expression of activated MEK1 in mouse skin induces hyperproliferative and inflamma tory lesions and inhibits epidermal differentiation, mimicking capabilities of squamous cell carcinomas. During the very same way, targeted expression of acti vated forms of C Raf or B Raf in several tissues of trans genic mice was shown to drive lung, skin, thyroid, and prostate tumorigenesis. Importantly, deinduc tion of activated B Raf expression in a conditional lung cancer mouse model contributes to dramatic tumor regression concomitant to inactivation of ERK1/2 signaling, sug gesting a dependency of B Raf induced lung tumors to the ERK1/2 pathway. Pre clinical pharmacological studies have demon strated that blockade of your ERK1/2 pathway with smaller molecule MEK1/2 inhibitors markedly restrains the proliferation of various carcinoma and leukemic cell lines by inducing cell cycle arrest and apoptosis.
In vivo studies even further established that administration of orally out there MEK1/2 inhibitors eli cits important tumor regression in mouse xenograft designs. The strategic place of MEK1 and MEK2 within the Ras dependent ERK1/2 pathway in con junction by using a promising pre clinical profile have professional vided robust rationale for informative post the growth of modest molecule inhibitors of MEK1/2 for chemotherapeutic intervention in cancer. Clinical advancement of MEK1/2 inhibitors PD98059 was the first compact molecule inhibitor of MEK1/2 to get disclosed in 1995. Biochemical stu dies indicated that PD98059 inhibits the exercise of both MEK1 and MEK2 isoforms, but fails to inhibit a panel of other Ser/Thr kinases. Two other potent inhi bitors of MEK1/2, U0126 and Ro 09 2210, were subsequently identified in cell based mostly assays. None of these compounds was moved to clinical evaluation since of their pharmaceutical limitations.
Nonetheless, PD98059 and U0126 have verified for being invaluable aca demic investigate resources to investigate the part on the ERK1/2 MAP kinase pathway selleck in usual cell physiology and disorder. To date, eleven MEK1/2 inhibitors happen to be examined clinically or are now undergoing clinical trial eva luation. The chemical structures of a few of these inhibitors are provided in Fig. four. CI 1040 The benzhydroxamate derivative CI 1040 was the very first MEK1/2 inhibitor to enter clinical trials. CI 1040 is usually a potent and highly selective inhibitor of MEK1 and MEK2 that was identified by screening a library compound with an inhibit the growth of colon carcinomas by as much as 80% in mouse xenograft versions. Importantly, anti tumor exercise was attained at effectively tolerated doses and correlated that has a reduction from the levels of phosphory lated ERK1/2 in excised tumors. A phase I study of orally administered CI 1040 was undertaken in 77 patients with advanced cancers.