title: Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3).
abstract: Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs. Macrocycles with an ether linker have potent JAK2 activity with the ether oxygen forming a hydrogen bond to Ser936. A hydrogen bond to the equivalent residues of JAK3 and most CDKs cannot be formed resulting in good selectivity for JAK2 over JAK3 and CDKs. Further optimization of the macrocyclic linker and side chain increased JAK2 and FLT3 activity as well as improving DMPK properties. The selective JAK2/FLT3 inhibitor 11 (Pacritinib, SB1518) has successfully finished phase 2 clinical trials for myelofibrosis and lymphoma. Another selective JAK2/FLT3 inhibitor, 33 (SB1578), has entered phase 1 clinical development for the non-oncology indication rheumatoid arthritis.
authors.affiliation: S*BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore, 117 528, Singapore. anders@colours.dk
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Anthony
authors.initials: A
authors.lastname: William
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Blanchard
authors.forename: Angeline
authors.initials: A
authors.lastname: Lee
authors.forename: Harish
authors.initials: H
authors.lastname: Nagaraj
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Eeling
authors.initials: E
authors.lastname: Teo
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tan
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Brian
authors.initials: B
authors.lastname: Dymock
mesh_terms: D000595:Amino Acid Sequence; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
chemical_list: C561234:11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; C573839:15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triazatetracyclo(18.3.1.1(2,5).1(14,18))hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene; D001952:Bridged-Ring Compounds; D006576:Heterocyclic Compounds, 4 or More Rings; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; D010100:Oxygen