title: Discovery of kinase spectrum selective macrocycle (16E)-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 (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.
abstract: Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
authors.affiliation: S BIO Pte. Ltd., 1 Science Park Road, No. 05-09, The Capricorn, Singapore Science Park II, 117528, Singapore. wanthony11@yahoo.com
authors.forename: Anthony D
authors.initials: AD
authors.lastname: William
authors.forename: Angeline C-H
authors.initials: AC
authors.lastname: Lee
authors.forename: Kee Chuan
authors.initials: KC
authors.lastname: Goh
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Blanchard
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Ee Ling
authors.initials: EL
authors.lastname: Teo
authors.forename: Harish
authors.initials: H
authors.lastname: Nagaraj
authors.forename: Chai Ping
authors.initials: CP
authors.lastname: Lee
authors.forename: Haishan
authors.initials: H
authors.lastname: Wang
authors.forename: Meredith
authors.initials: M
authors.lastname: Williams
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sun
authors.forename: Changyong
authors.initials: C
authors.lastname: Hu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Mohammed Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Wood
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
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; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D051941:fms-Like Tyrosine Kinase 3; D053616:Janus Kinase 3; D018844:Cyclin-Dependent Kinases