The primary objective of the present project is to perform a hit-to-lead program (H2L) and further to develop a preclinical drug candidate. The outcome of the project is expected to be a preclinical drug candidate. Lead-backups will also be secured in cas e of future failure in a downstream process. The preclinical candidate will be the starting point to an investigational new drug (IND) program, at which point an IND application will be filed.We have identified and characterized the function of the gene and the protein CalphaS. CalphaS is only expressed one place in the body, namely the sperm cell. We and others have shown using knock-out (KO) mice that CalphaS regulates sperm cell motility and male fertility. Through an early drug discovery program, we have verified the protein CalphaS as a promising target for a male contraceptive. In this work we have developed functional assays on live sperm cells, biochemical assays and solved the 3D-structure of CalphaS by X-ray crystallography. In collaboration w ith our world renovated partner Evotec AG, we have performed a virtual screen (VS) of about 3 million chemical compounds. A HTS with CalphaS as a target will be performed in January 2008.We want to further develop the primary hits from the HTS into a le ad compound and finally to a preclinical drug candidate. The hit to candidate program will be an iterative process between X-ray co-crystallography (CalphaS and hits), bioinformatics, medicinal chemistry, toxicology, functional assays on live sperm cells and testing on animal models.Spermatech is at present time in an early phase of drug discovery. Early drug discovery is intimately connected with a high risk. The scientific risk is gradually reduced as compounds are developed from hit to lead to drug c andidate to drug. Moving from hit to drug candidate is a major challenging step in the complex path of drug discovery.