{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T23:44:28Z","timestamp":1782776668686,"version":"3.54.5"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":95,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Manual synthesis of small molecules can represent a rate-limiting step in medicinal chemistry. This study describes the application of an automated, modular synthesis platform (\u2018Chemputer\u2019) to a drug discovery project targeting a model of KRAS-mutant colorectal cancer (K-CRC). A 4-anilinoquinazoline-based compound library was synthesized using automated and digitized protocols for nucleophilic aromatic substitution (SnAr) and Suzuki cross-coupling reactions. Chemical synthesis is guided by phenotypic screening of a transgenic\n                    <jats:italic>Drosophila<\/jats:italic>\n                    line engineered to model the genetic profile of a patient\u2019s K-CRC tumour. This integrated system enables iterative synthesis and screening cycles. An initial run identified the hit compound AP2-83, which strongly improves animal survival. Kinase profiling and genetic validation find that AP2-83 activity is mediated in part through inhibition of CLK1 and PI3K. A subsequent optimisation effort, informed by these results, produced AP4-43. AP4-43 demonstrates increased efficacy in the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model and greater potency than regorafenib in a mammalian CRC organoid growth assay. Functional analysis indicates AP4-43 acts as a multi-kinase inhibitor, with its enhanced activity associated with the inhibition of a network including CLK1 and NEK4. This work demonstrates the utility of a digital synthesis platform for generating and optimising lead compounds in a complex, preclinical drug discovery context.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-09873-8","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:37:56Z","timestamp":1774589876000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemical programming of kinase inhibitors in a modular chemputer-based system"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1607-4691","authenticated-orcid":false,"given":"Hammed A.","family":"Badmos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrisor-Alin","family":"Pirvan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Klimareva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8035-5757","authenticated-orcid":false,"given":"Leroy","family":"Cronin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5297-450X","authenticated-orcid":false,"given":"Ross","family":"Cagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"9873_CR1","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/s41586-023-06388-8","volume":"620","author":"K Trajanoska","year":"2023","unstructured":"Trajanoska, K. et al. 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