Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma
J. Med. Chem. 2022, 65, 15856−15877
This is a biased pick – we wrote a review on SOS1 inhibitors a year or so ago – so there you go [https://doi.org/10.1080/13543776.2021.1952984]. At the start of my career the pharma company I worked at had a library – yes physical books! I would take home the journals to read overnight or the weekend. I would look at tables and data, and deliberately try and work out the SAR before reading the text or skipping forward so that my brain got trained. This paper has a good number of compounds and SAR tables so is quite good for performing that exercise. Overall it is a description of a ‘fast-follow’ / ‘MeToo’ approach to drug hunting – start from a known inhibitor and modify to gain a novel / inventive compound and improve properties. If you did not known SOS1 compound, there is a distinct binding pocket that takes an aniline, with 3-CF3 group – less than desirable as we would worry about toxicity. If nothing else note the 1-difluoro-methyl-2-fluoro-benzene ring replacement group. It would be right to note the hydrogen of the difluoro-methyl group – is this a weak H-bond group? Does this mimic the NH2 or is it an optimised group for the pocket so the NH2 is not required? The paper concerns the extension of the central ring where it has been shown there is room for variation (see our SOS1 review). A tricycle become a tetracycle with an electrophilic nitrile terminal group – how interesting?