In Alex's class we recently discussed small molecule inhibitors of DNA. One of the small molecules targeted the VEGF pathway in the hope of reducing tumor growth. As we discussed, DNA small molecule inhibitors must be able to not only penetrate the cell and nucleus, but also access the DNA wrapped around the histones.
Small molecules that can inhibit cellular receptors are the most widely used therapeutic on the market due to the easy accessibly of the receptor on the outside of the cell. This paper from GlaxoSmithKline (RTP) describes the discovery of a kinase inhibitor that targets a VEGF receptor, which has been approved by the FDA to treat renal cell carcinoma (RCC).
I think this paper is a good example of how much optimization is required for drugs to begin clinical trials. Something I found interesting was the addition of sterically hindering side groups to decrease the IC50 as discussed in class.
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