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.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Computer Simulation
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Dogs
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Drug Screening Assays, Antitumor
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Female
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Janus Kinase 3 / antagonists & inhibitors*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microsomes, Liver / metabolism
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Models, Molecular
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Neoplasm Transplantation
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
Substances
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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
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Antineoplastic Agents
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Heterocyclic Compounds, 4 or More Rings
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fms-Like Tyrosine Kinase 3
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Janus Kinase 3
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Cyclin-Dependent Kinases