title: 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).
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.
authors: S*BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore, 117 528, Singapore. anders@colours.dk
authors: Anders
authors: A
authors: Poulsen
authors: Anthony
authors: A
authors: William
authors: Stéphanie
authors: S
authors: Blanchard
authors: Harish
authors: H
authors: Nagaraj
authors: Meredith
authors: M
authors: Williams
authors: Haishan
authors: H
authors: Wang
authors: Angeline
authors: A
authors: Lee
authors: Eric
authors: E
authors: Sun
authors: Ee-Ling
authors: EL
authors: Teo
authors: Evelyn
authors: E
authors: Tan
authors: Kee Chuan
authors: KC
authors: Goh
authors: Brian
authors: B
authors: Dymock
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C570909:14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene; D006576:Heterocyclic Compounds, 4 or More Rings; D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; D018844:Cyclin-Dependent Kinases; D009584:Nitrogen