Terpenoid Therapeutics

Terpenoid currently has two projects to discover novel drugs. One project is focused on discovering small molecule inhibitors of geranylgeranyl diphosphate synthase, a novel target with applicability towards cancer and other indications. Another project is focused on the schweinfurthins, a family of novel cytotoxic agents with applicability towards cancer.

Terpenoid Bisphosphonates

Terpenoid's bisphosphonate project is based on proprietary terpenoid-modified bisphosphonate inhibitors of geranylgeranyl diphosphate synthase (GGDPS), a novel target for which there is no approved drug at this time. Terpenoid predicts that inhibition of GGDPS will result in efficacy in the treatment of primary tumors and metastases (including, but not limited to, bone metastases).

The Terpenoid founders, working at the University of Iowa, have synthesized compounds of a novel chemical class that inhibit GGDPS selectively, resulting in interesting biological effects in vitro and in vivo. The enzyme GGDPS forms a key product of the isoprenoid pathway, GGPP (geranylgeranyl diphosphate) (a twenty carbon compound), through the addition of isopentenyl diphosphate (five carbons) to farnesyl diphosphate (fifteen carbons). GGPP is then added to specific proteins by geranylgeranyl transferase I or Rab geranylgeranyl transferase in a post-translational modification process known as geranylgeranylation. This process is critical to maintaining differential intracellular membrane localization and proper functioning of these proteins. Among the proteins that are geranylgeranylated are members of the Ras superfamily of small GTPases which regulate important cellular processes, including proliferation (Ras, Rap1a), migration and metastasis (Rho/Rac), and vesicular trafficking (Rab). All of these proteins are important in cancer and osteoporosis.

Terpenoid Schweinfurthins

Terpenoid's schweinfurthin project is focused on discovering and developing a drug with activity against primary tumors and metastases. This project is based on rare schweinfurthin natural products whose unique profile of anti-cancer activity was first reported by the National Cancer Institute in 1998.

Terpenoid Therapeutics has synthesized numerous compounds in this family, including those which were originally identified in an extract of the Cameroonian plant Macaranga schweinfurthii and a number of synthetic analogues. A team of scientists at the NCI isolated three compounds from this plant with anti-cancer effects but subsequent efforts to obtain more of these compounds from the natural source met with limited success. The most interesting facet of the schweinfurthins' activity is the differential pattern of activity observed in the NCI 60 cell line panel, where nanomolar concentrations are active against some cancer cell lines, while other cell lines are resistant at much higher concentrations. The compounds likely have a mechanism of action different from anti-cancer compounds now in clinical use. The combination of this potentially unique mode of anti-cancer activity and the problems of securing material for further testing led one of the Terpenoid founders to initiate a program aimed at synthesizing these compounds from commercially available materials.