Abstract
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
MeSH terms
-
Adenosine Triphosphate / chemistry
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / pharmacokinetics
-
Antineoplastic Agents / pharmacology
-
Binding Sites
-
Bridged-Ring Compounds / chemical synthesis*
-
Bridged-Ring Compounds / pharmacokinetics
-
Bridged-Ring Compounds / pharmacology
-
Cell Line, Tumor
-
Dogs
-
Drug Screening Assays, Antitumor
-
Humans
-
In Vitro Techniques
-
Janus Kinase 2 / antagonists & inhibitors*
-
Lymphoma / drug therapy*
-
Mice
-
Mice, Nude
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Neoplasm Transplantation
-
Primary Myelofibrosis / drug therapy*
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Rats
-
Solubility
-
Transplantation, Heterologous
-
Transplantation, Homologous
-
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
Substances
-
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
-
Antineoplastic Agents
-
Bridged-Ring Compounds
-
Pyrimidines
-
Adenosine Triphosphate
-
fms-Like Tyrosine Kinase 3
-
Janus Kinase 2