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Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3)

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Abstract

A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring-closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan-CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials.

Structure of SB1317 (left). SB1317 docked into CDK2 (right)

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Authors and Affiliations

  1. S*BIO Pte Ltd, 1 Science Park Road, #05–09 The Capricorn, Singapore Science Park II, Singapore, 117 528, Singapore

    Anders Poulsen, Anthony William, Stéphanie Blanchard, Harish Nagaraj, Meredith Williams, Haishan Wang, Angeline Lee, Eric Sun, Ee-Ling Teo, Evelyn Tan, Kee Chuan Goh & Brian Dymock

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  1. Anders Poulsen
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  2. Anthony William
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  3. Stéphanie Blanchard
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  4. Harish Nagaraj
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  5. Meredith Williams
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  6. Haishan Wang
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  7. Angeline Lee
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  8. Eric Sun
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  9. Ee-Ling Teo
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  10. Evelyn Tan
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  11. Kee Chuan Goh
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  12. Brian Dymock
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Correspondence to Anders Poulsen.

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Poulsen, A., William, A., Blanchard, S. et al. Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3). J Mol Model 19, 119–130 (2013). https://doi.org/10.1007/s00894-012-1528-7

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  • DOI: https://doi.org/10.1007/s00894-012-1528-7

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