ABSTRACT
Thirty-six novel acylurea connected straight chain hydroxamates were designed and synthesized. Structure-activity relationships (SAR) were established for the length of linear chain linker and substitutions on the benzoylurea group. Compounds 5g, 5i, 5n, and 19 showed 10-20-fold enhanced HDAC1 potency compared to SAHA. In general, the cellular potency pIC(50) (COLO205) correlates with enzymatic potency pIC(50) (HDAC1). Compound 5b (SB207), a structurally simple and close analogue to SAHA, is more potent against HDAC1 and HDAC6 compared to the latter. As a representative example of this series, good in vitro enzymatic and cellular potency plus an excellent pharmacokinetic profile has translated into better efficacy than SAHA in both prostate cancer (PC3) and colon cancer (HCT116) xenograft models.
Subject(s)
Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Urea/pharmacology , Animals , Cell Line, Tumor , Histone Deacetylase Inhibitors/chemistry , Humans , Hydroxamic Acids/chemistry , Kinetics , Mice , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model.
Subject(s)
Acrylamides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Histone Deacetylase Inhibitors , Acrylamides/administration & dosage , Acrylamides/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor/methods , Female , HCT116 Cells , Histone Deacetylases/metabolism , Humans , Mice , Mice, Nude , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Janus Kinase 2/antagonists & inhibitors , Lymphoma/drug therapy , Primary Myelofibrosis/drug therapy , Pyrimidines/chemical synthesis , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Binding Sites , Bridged-Ring Compounds/pharmacokinetics , Bridged-Ring Compounds/pharmacology , Cell Line, Tumor , Dogs , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Solubility , Transplantation, Heterologous , Transplantation, HomologousABSTRACT
A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC(50)), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC(50)), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.