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1.
J Clin Invest ; 134(8)2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38618957

ABSTRACT

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.


Subject(s)
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Animals , Humans , Mice , Mice, Transgenic , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Protein-Tyrosine Kinases , Receptors, Antigen, T-Cell/genetics , Signal Transduction , STAT5 Transcription Factor/genetics
2.
EMBO Mol Med ; 14(12): e15200, 2022 12 07.
Article in English | MEDLINE | ID: mdl-36341492

ABSTRACT

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL.


Subject(s)
Lymphoma, T-Cell, Cutaneous , p21-Activated Kinases , Animals , Mice , Genomics , Heterografts , Lymphoma, T-Cell, Cutaneous/drug therapy
3.
J Pers Med ; 2(1): 15-34, 2012 Mar 07.
Article in English | MEDLINE | ID: mdl-25562700

ABSTRACT

Oncology is one of the most important fields of personalized medicine as a majority of efforts in this field have recently centered on targeted cancer drug development. New tools are continuously being developed that promise to make cancer treatment more efficacious while causing fewer side effects. Like most industries, the biopharmaceutical industry is also following certain global trends and these are analyzed in this article. As academia and industry are mutually dependent on each other, researchers in the field should be aware of those trends and the immediate consequences for their research. It is important for the future of this field that there is a healthy relationship among all interested parties as the challenges of personalized medicine are becoming ever more complex.

4.
Bioorg Med Chem Lett ; 20(22): 6379-83, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20934334

ABSTRACT

A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.


Subject(s)
Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Pyrazoles/pharmacology , Caco-2 Cells , Catalytic Domain , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular
5.
Bioorg Med Chem Lett ; 19(19): 5547-51, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19716697

ABSTRACT

An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.


Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Animals , Drug Discovery , HeLa Cells , Humans , I-kappa B Kinase/metabolism , Lipopolysaccharides/pharmacology , Mice , NF-kappa B/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Signal Transduction , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism
6.
Bioorg Med Chem Lett ; 18(23): 6218-21, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18930400

ABSTRACT

Based on the information from molecular modeling and X-ray crystal structures, the kinase specificity pocket of ITK could be occupied upon extension of the right-hand-side of the 2-benzimidazole core of the inhibitors. 2-Aminobenzimidazoles with a trans-stilbene-like extension were designed and synthesized as novel ITK antagonists. Significant improvement on binding affinity and cellular activity were obtained through the trans-stilbene-like antagonists. Several compounds showed inhibitory activity in an IL-2 functional assay.


Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Stilbenes/chemistry , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
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