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Case Study 1: Novel abl1 inhibitors

The discovery of BCR-abl inhibitors has revolutionised the treatment of chronic myeloid leukemia (CML).  The first BCR-abl inhibitor to be launched, imatinib shows robust clinical efficacy and is now a front line therapy for the treatment of CML.  However, a small number of patients on imatinib therapy relapse and become imatinib-resistant.  Second generation inhibitors nilotinib and dasatinib have shown efficacy against many clinically relevant mutations in the abl active site.  However, imatinib, nilotinib and dasatinib all show poor activity against the T315I 'gatekeeper' mutant, which is responsible for around 15-20% of all clinical mutants.  Recently, a third generation BCR-abl inhibitor ponatinib has shown impressive clinical efficacy in patients expressing the T315I mutation, and the discovery of ponatinib has recently been disclosed.  Despite several years of research, the ability of abl kinase mutations to confer resistance against the first and second generation agents shows that BCR-abl is still an attractive drug target.

Together with our partners Sandexis, we set out to explore chemistry space specifically designed to discover molecules with a similar activity profile to ponatinib against a range of clinically relevant abl mutants with the CyclOps™ platform. CyclOps was set up to explore a range of kinase activities in parallel as well as measuring CHI logD of all synthesised molecules in real time. The measured results for each compound were fed back into our proprietary algorithm before the next test compound was designed and synthesised in our fully automated process. After 170 hours operation 4 compounds with a novel chemotype were discovered with the required activity profile and drug-like physical properties. Fast scale up using flow chemistry provided material for further profiling which showed the desired activity profile against a range of abl mutants.

The results of this project were published recently in the Journal of Medicinal Chemistry


See also:

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Madin, A.; 2016; UK Automated Synthesis Forum; Optimisation of a screening hit with the Cyclofluidic CyclOps Platform: A User Perspective
Czechtizky W, Dedio J, Desai B, Dixon K, Farrant E, Feng Q, Morgan T, Parry DM, Ramjee MK, Selway CN, Schmidt T, Tarver GJ, Wright AG. Integrated Synthesis and Testing of Substituted Xanthine Based DPP4 Inhibitors: Application to Drug Discovery. ACS Med Chem Lett. 2013 Jun 10;4(8):768-72. doi: 10.1021/ml400171b.
Lambert GK, Duhme-Klair AK, Morgan T, Ramjee MK. The background, discovery and clinical development of BCR-ABL inhibitors. Drug Discov Today. 2013 Oct;18(19-20):992-1000. doi: 10.1016/j.drudis.2013.06.001.
Desai B, Dixon K, Farrant E, Feng Q, Gibson KR, van Hoorn WP, Mills J, Morgan T, Parry DM, Ramjee MK, Selway CN, Tarver GJ, Whitlock G, Wright AG. Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform. J Med Chem. 2013 Apr 11;56(7):3033-47. doi: 10.1021/jm400099d.