Compound Technology

TECHNOLOGY:
Selective pro-apoptotic drug for treating pre-cancerous conditions or malignant disease

DESCRIPTION:
Clinical studies have shown that the nonsteroidal anti-inflammatory drug (NSAID), sulindac is highly effective for treating colon adenomas in patients with either sporadic or familial adenomatous polyposis. Unfortunately, gastrointestinal toxicity and other side effects limit the use of sulindac and other NSAIDs for treating pre-cancerous conditions, as well as malignant disease. Researchers at the Southern Research Institute (Birmingham, AL) have developed a novel technology by chemically modifying sulindac to reduce its toxicity, while improving anticancer activity . Studies with a lead compound, designated as SRI 21009, have demonstrated strong antitumor efficacy in several experimental animal models and desirable pharmacokinetic properties. SRI 21009 is in preclinical development at Southern Research and several other research centers around the United States. This technology has the potential to be first in a class of new drugs for the treatment of pre-cancerous conditions or malignant disease.

Suggested Uses:

• Treatment for patients with pre-cancerous conditions of the colon, such as sporadic or familial adenomatous polyposis.
• Prevention of colon cancer in patients at high risk for developing malignant disesase, such as those with inflammatory bowel disease, including Crohn's disease or ulcerative colitis.
• Treatment of pre-cancerous conditions of other tissues, such as skin, breast, esophagus, bladder, lung, head and neck, cervix, and prostate.
• Treatment of minimal residual malignant disease, for example, in patients diagnosed with malignant disease and treated with surgery, radiation or chemotherapy, but who remain at risk of disease progression.
• Prevention of cancer in normal individuals who are at high risk of disease occurrence, including those with a genetic predisposition to cancer such as familial melanoma or a family history of cancer, or those who express certain cancer-causing mutations.
• Prevention of cancer in individuals at high risk of developing cancer due to exposure to carcinogens in the environment, including cigarette smoke.

Advantages:

• Proprietary sulindac derivatives that do not inhibit cyclooxygenases and should not exhibit side effects associated with NSAIDs and COX-2 selective inhibitors including gastrointestinal, renal, and cardiovascular toxicity.
• Potent and selective antiproliferative and apoptosis-inducing activity on human tumor cells to target tumor cells.
• Oral bioavailability with desirable pharmacokinetic properties for twice-a-day dosing as a tablet, capsule or liquid suspension.
• Effective in experimental models of cancer chemoprevention.
• Effective in xenograft models alone and in combination with chemotherapy.

TECHNICAL DESCRIPTION

Sulindac has shown promising antineoplastic activity in clinical studies, although toxicity resulting from cyclooxygenase (COX) inhibition and depletion of physiologically important prostaglandins limits its use for cancer indications. To identify specific chemical properties of sulindac that could be altered, molecular modeling studies were performed, which revealed that the carboxylate moiety is essential for COX-1 and COX-2 binding. A panel of sulindac derivatives with carboxylic acid modifications were synthesized and evaluated for tumor cell growth inhibitory activity. A series of derivatives were found to lack COX-1 and COX-2 inhibitory activity, but potently inhibit the in vitro growth of human tumor cell lines. The growth inhibitory activity of one derivative, SRI 21009, was found to be associated with the ability to selectively induce apoptosis (programmed cell death). In a mouse model of colon tumorigenesis that displays similar genetic aberrations as humans, SRI 21009 effectively inhibited the formation of colon tumors. SRI 21009 also strongly inhibited colon tumor growth in a mouse xenograft model to an extent comparable to the chemotherapeutic drug irinotecan. SRI 21009 also enhanced the anticancer activity of irinotecan.. These results demonstrate that SRI 21009 or a related analog may have potential utility to treat patients with pre-cancerous conditions or malignant disease.

DEVELOPMENT STATUS:Preclinical development

PATENT PROTECTION: US Patent Pending 11/649,373

REFERENCE NUMBER: S0283

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