The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play a major role in the proliferation and survival of many types of cancer cells, including breast, prostate, and colorectal carcinomas. Therefore, finding novel ways to specifically inhibit ERK proteins may lead to the development of new chemotherapeutic agents. ERK proteins contain two putative docking domains that are important for regulating the specificity and efficiency of ERK interacting substrate proteins. We hypothesize that small molecular weight compounds that interfere with ERK docking domains will selectively block ERK interactions with substrate proteins and inhibit cell proliferation. For these studies, we will use computer aided drug design (CADD) to identify potential lead compounds that interact with ERK docking domains. These compounds will be tested for their ability to selectively inhibit ERK-specific phosphorylation of substrate proteins. Compounds that show inhibitory activity will be tested for specific binding to the ERK docking domain regions and effectiveness in blocking ERK-dependent cell proliferation. At the end of the proposed studies, we expect to identify several compounds that bind to the ERK docking domains and specifically inhibit ERK-mediated phosphorylation. These compounds will then be used in further development of therapeutic agents for treating cancers containing elevated levels of ERK activity. These studies represent a novel approach for developing compounds that selectively block ERK activation of proteins involved in cancer cell proliferation. [unreadable] [unreadable]