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Pre-clinical data suggests bone drug candidate

By Wai Lang Chu , 11-Oct-2005

Enzo Biochem, announced that pre-clinical experiments with its small molecule candidate suggests it would have applications in strengthening bones weakened by age or as a consequence of certain medications.

The candidate aims to fill an unmet need that has suffered from a lack of effective drugs that could strengthen bones without the debilitating side effects that have become characteristic of these types of drug.

A team made up of scientists up from Enzo Biochem, the University of Connecticut Health Centre and St. Jude Hospital, reported delivery of the candidate IIIC3 to laboratory animals resulted in bone like tissue growth and increases in bone mass.

The compound has been shown to block the binding of Dkk1, a factor that interferes with the action of a protein (Wnt) that stimulates increased bone density.

This molecule was discovered through use of an innovative combination of structural and molecular biology involving "in silico" virtual screening and biological assays.

Both human and mouse genetic evidence indicates that the Wnt signaling has an important role in bone formation. The study of the mechanism underlying the high bone mass mutation of Wnt coreceptor LRP5 (G171V) suggested that this mutation reduces Dkk1-mediated antagonism.

"This finding allows us to hypothesize that disruption of the interaction between LRP5 and Wnt antagonist Dkk may lead to an increase in bone formation," said the study.

The study detailed the first-round of screening, which yielded 50 candidate compounds. They were able to obtain 17 of them for testing their ability to inhibit Dkk binding to LRP5.

A second-round screening for compounds was then carried out. The team obtained and tested 19 of top ranked compounds and found that one of them (IIC8) was able to reverse Dkk-mediated inhibition of Wnt signalling at low uM concentrations.

The third-round virtual screening was carried out based on the structure of IIC8 and yielded a compound (IIIC3) that can reverse Dkk-mediated antagonism of Wnt signalling at the high nM range.

Both IIC8 and IIIC3 are able to block the binding of Dkk1-AP to LRP5 or LRP6. To test their effects on bone formation, IIC8 and IIIC3 were injected locally at mouse calvaria. Both compounds showed strong stimulatory effects on bone formation

Enzo Biochem said that while additional laboratory studies remain, a successful compound would have applications in preventing fractures.

The products emanating from this technology could potentially provide therapy for bone disorders, including bone loss, fractures, abnormalities, diseases and other applications.

This technology relates to the modulation of signalling pathways in cell development and differentiation by signalling proteins and small molecular compounds or drugs.

These proteins and drugs have been shown to act in osteoblasts (the bone forming cells) in their pathway to mature bone cells.

Enzo and collaborators in a paper presented at the American Society for Bone and Mineral Research Conference in Nashville.