(C) Cyclofluidic 2016 - Dr Steven V. LeyCyclofluidic: Automated Molecule Discovery with OPS TM

Cyclofluidic has a vision of revolutionising discovery, solving medicinal chemistry problems at speed, through integration of flow chemistry, purification, screening and design in a true closed loop. We are aiming to:

  • Become the partner of choice with the pharmaceutical, biotech and not-for-profit drug discovery
  • Translate our passion for drug discovery into pre-clinical molecules with the highest chance of becoming innovative medicines
  • Impact on drug discovery through our innovation in science and business
  • Develop partnerships with our collaborators, leveraging the CylOps™ platform to solve medicinal chemistry problems at speed

Case Study: 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.

Source: Cyclofluidic Ltd. 

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