Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance immunotherapy

• Derun Li^a, Hongjun Zhang^a, Thomas W. Lyons^a, Theodore A. Martinot^a, Abdelghani Achab^a, Min lu^a, Lisa M. Nogle^a, Spencer McMinn^a, Matthew J. Mitcheltree^a, Matthew Childers^a, Qinglin Pu^a, Symon Gathiaka^a, Anand Palani^a, Kalyan Chakravarthy^a, Amy D. DeCastro^a, Jennifer O'Neil^a, Roshi Afshar^a, Nicole C. Walsh^a, Peter W. Fan^a, Mangeng Cheng^a, Richard Miller^a, Amy Doty^a, Rachel Palte^a, Hai-Young Kim^a, Josep Saurí^a, Adam Beard^a, Christopher Brynczka^a and Christian Fischer^a

• ^aMerck Research Laboratory, Boston, MA.

Arginase overexpression has been associated with poor survival rates in advanced cancer patients treated with Keytruda. High levels of Arginase may lead to a depletion of arginine within the tumor microenvironment, inhibiting the immune response. Thus, arginase inhibition has the potential to greatly enhance immunotherapy treatment. Discovering novel arginase inhibitors was met with several challenges including analyzing/purifying extremely polar chemical matter without chromophores, synthetically challenging space, and poor bioavailability of compounds with ClogP less than minus two.

Cross-functional collaborations and innovations rapidly overcame these challenges. Structural chemistry and modeling guided the design of novel arginase inhibitors. Analytical and purification groups developed innovative analytical/purification methods. Novel technologies including ReatIR and Vapourtec flow system, provided key intermediates to enable chartering into synthetically challenging space. Through creative cyclization strategies and active transport strategy to improve bioavailability, the team ultimately delivered a diverse set of potent and extremely synthetically challenging arginase inhibitors to study the potential of arginase inhibition. Preliminary in vivo evaluation showed single agent efficacy in an EMT6 model. These arginase inhibitors have the potential to enhance immunotherapy.

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