Standard hormonal therapy with currently available anti-androgens and LHRH analogs becomes ineffective in the hormone-refractory stage of prostate cancer due to the changes in androgen receptor signaling axis in prostate cancer cells. To develop effective therapies against hormone-refractory prostate cancer, novel agents targeting multiple points at the cellular signaling cascades are needed in order to produce the maximal therapeutic efficacy against late stage prostate cancer. In this dissertation work, we have presented the design and development of novel agents targeting three key signaling pathways towards their ultimate development into the effective therapies against hormone refractory prostate cancer. Specifically, we have discovered and designed a diverse array of novel molecules targeting the AR signaling pathway, the sarco-endoplasmic reticulum calcium ATPase pump driven calcium homeostasis and the proteolytic activity of prostate specific antigen .