The Sonic Hedgehog (SHH) signaling pathway is required during embryogenesis for cell differentiation and growth; however, medulloblastoma, a pediatric malignancy in the cerebellum, as well as glioblastoma multiforme (GBM), a malignant and invasive adult brain tumor, also require SHH signaling for growth. As SHH signaling remains inactive in healthy adult cells, this pathway provides an excellent target for chemotherapeutics. Cyclopamine, a naturally occurring alkaloid, inhibits the SHH pathway at the level of Smoothened (SMO) and has demonstrated reduced tumor growth in vivo. However, this alkaloid is metabolically unstable. Analysis of the hydrophobic core of cyclopamine revealed a similarity to the steroidal ABCD ring system. Using estrone as a hydrophobic surrogate, we have synthesized readily accessible and metabolically stable analogs to inhibit the SHH pathway. Using computational analysis in conjunction with high-throughput biological evaluation, we are continuing to design and synthesize novel antagonists of the SHH pathway in hopes to further understand the binding pocket of SMO. To this end, we have made significant progress towards elucidating which aspects of the molecules may be required for potency and have identified a new class of compounds that exhibit potency ten times that of cyclopamine.