myeloma. For example, studies of epithelial cancers have demonstrated that tumor cells secrete Shh ligand to signal adjacent growth factors production by stromal cells which leads to angiogenesis, tumor cell proliferation, and tumor cell survival. With this in mind, one can imagine cyclopamine as a way of attenuating cancer's mechanism. However, while cyclopamine has been demonstrated to inhibit tumor growth in mouse xenograft models, it never reached therapeutic potential as it caused many side effects including weight loss, dehydration, and death in mouse models. Having said that, two functional analogs of cyclopamine have been approved by the FDA; vismodegib in 2012, and sonidegib in 2015. Furthermore, vismodegib was the first Shh pathway drug approved for treating cancer. While cyclopamine and vismodegib do not appear very similar, the development of vismodegib revealed which aspects of cyclopamine give it functionality and used those results to make vismodegib. For example, the added chlorine group in Vismodegib gives the drug a much higher solubility than cyclopamine – low solubility is a hindrance towards making cyclopamine a practical drug. The development of vismodegib revealed structure activity relationships (SAR), and determined that hydrogen bonding in two sites, as well as solubility, impact the effectiveness of the drug. Specifically speaking, the two hydrogen bonds work in opposite ways; at one site a tyrosine residue on the Smoothened receptor offers a proton to be accepted whereas a separate arginine residue works as a hydrogen bond acceptor. While the accepting group is more impactful, having both makes for stronger binding. See also Saridegib (also known as IPI-926), a semisynthetic analog of cyclopamine Vismodegib, an artificial Hh signaling inhibitor Sonidegib, an artificial Hh signaling inhibitor Steroidal alkaloid, the family of molecules cyclopamine falls in References Further reading Cancer Drug Behind Cyclops Birth?, Wired News Jervines Teratogens Spiro compounds Secondary alcohols Nitrogen heterocycles Oxygen heterocycles Plant toxins