Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma.

Simple Summary: Drugs work by binding to a specific 3D structure on a protein. Drug discovery has historically been driven by prior knowledge of function, either of a protein or chemical. This knowledge of function then drives investigations to probe chemical/protein interactions. We undertook a different approach. We first identified unique 3D structures, agnostic of function, and investigated whether they could lead us to innovative therapeutics. Using a synchrotron-based X-ray source, we first determined high-resolution structures of hundreds of proteins. With a supercomputer running analytical programs created by us, we identified novel 3D structures and screened for chemicals binding them. We then tested their ability to inhibit cancer growth without damaging normal cells. We identified a potent inhibitor of a deadly cancer, melanoma. It was not toxic to normal cells even at 2100-fold higher doses. It worked by inducing anoikis, a fundamental process of known importance for cancer. Therapeutics that selectively induce anoikis are needed. In summary, we demonstrate the power of using a 3D protein structure as the starting point to discover new biology and drugs. Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable. [ABSTRACT FROM AUTHOR]