Hoechst Marion Roussel on Thursday signed its fifthsignificant collaboration in the past month as it agreed toa deal potentially worth $38 million to ProScript Inc.

Hoechst's latest deal gains it access to technologyintended to inhibit enzymes in ubiquitin-proteasomepathways, a biological process for cell signaling believedto play an important part in inflammatory response andcell division.

It is the first corporate collaboration for ProScript, ofCambridge, Mass., which has been focusing on theubiquitin-proteasome pathway since its founding in late1992. Company officials said the pathway plays its rolethrough the activation of NF-kappaB, which isresponsible for transcriptionally activatingproinflammatory cytokines, cell adhesion molecules andenzymes. The pathway also regulates cell division bymaintaining appropriate levels of p53 and mitotic cyclins.

"We've come to realize only in the last year or two thatthe ubiquitin-proteasome pathway is a unique biologicalprocess that interprets cell signaling," said RichardBagley, chairman and CEO of ProScript (formerly calledMyoGenics). "We are virtually the only company that hasan expertise in that pathway and the only one with smallmolecule inhibitors of it."

Hoescht, of Frankfurt, Germany, on Monday agreed to adeal worth up to $40 million with Ariad PharmaceuticalsInc., of Cambridge, Mass., related to Ariad's work indeveloping molecules that affect intracellular signaltransduction pathways. In October Hoechst agreed to payup to $160 million to Cell Genesys Inc., of Foster City,Calif., for the latter's T cell gene therapy for AIDS. AndHoechst followed that deal by agreeing to pay up to $50million for the establishment of a genomics infrastructurethrough deals with Incyte Pharmaceuticals Inc., of PaloAlto, Calif., and Lynx Therapeutics Inc., of Hayward,Calif.

ProScript has raised about $13 million to date, primarilyby venture firms HealthCare Investment Corp. andDillon, Read Venture Capital. It became operational thespring of 1993, and has 27 employees. The work sprangmostly from work done by professors Thomas Maniatisand Alfred Goldberg of Harvard University and HarvardMedical School, respectively.

In the deal, ProScript will receive $15 million in equityinvestments and research support from Hoechst, andcould receive up to another $23 million uponachievement of milestones and the exercising by Hoechstof additional product rights. Of the original $15 million,more than half is equity, Bagley said, and gives Hoechst astake of less than 20 percent.

In return Hoechst received exclusive worldwide rights totwo classes of small-molecule proteasome inhibitors forinflammation and cancer. Hoechst will fund alldevelopment activities, and pay ProScript royalties onsales.

"We have advanced to the point where we have orallyactive small molecule inhibitors of proteasome," Bagleysaid. "We've put our lead molecules through multipleanimal models of rheumatoid arthritis and inflammatorybowel disease. We'll be in a position to file our firstinvestigational new drug application as early as late nextyear."

Bagley said the proteasome is a structure within the cell,and activity associated with the degradation of proteinsby the proteasome generally is referred to as theubiquitin-proteasome pathway. The end products fromprotein degradation control the inflammatory processthrough the activation of NF-kappaB, and the mitoticprocess by regulating levels of p53 and cyclins.

After NF-kappaB is activated by the proteasome, Bagleysaid, it translocates to the nucleus, binds DNA and causesthe gene transcription of the inflammatory mediators.That's an appropriate response to infection or amechanical trauma, but in the case of autoimmunedisease, it's an inappropriate response, he said.

"The strategy of the company is, therefore, to block theproteasome, partially and transiently, to return thatabnormal response back to a normal state," Bagley said. n

-- Jim Shrine

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