NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3.
BACKGROUND
Human or animals lacking either JAK3 or the common gamma chain (gammac) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigenesis. Recent studies identified activating JAK3 mutations in patients with various hematopoietic malignancies, including acute megakaryoblastic leukemia. Importantly, functional analyses of some of those JAK3 mutations have been shown to cause lethal hematopoietic malignancies in animal models. These observations make JAK3 an ideal therapeutic target for the treatment of various human diseases. To identify novel small molecule inhibitors of JAK3, we performed structure-based virtual screen using the 3D structure of JAK3 kinase domain and the NCI diversity set of compounds.


RESULTS
We identified NSC114792 as a lead compound. This compound directly blocked the catalytic activity of JAK3 but not that of other JAK family members in vitro. In addition, treatment of 32D/IL-2Rbeta cells with the compound led to a block in IL-2-dependent activation of JAK3/STAT5 but not IL-3-dependent activation of JAK2/STAT5. Consistent with the specificity of NSC114792 for JAK3, it selectively inhibited persistently-activated JAK3, but failed to affect the activity of other JAK family members and other oncogenic kinases in various cancer cell lines. Finally, we showed that NSC114792 decreases cell viability by inducing apoptosis through down-regulating anti-apoptotic gene expression only in cancer cells harboring persistently-active JAK3.


CONCLUSIONS
NSC114792 is a lead compound that selectively inhibits JAK3 activity. Therefore, our study suggests that this small molecule inhibitor of JAK3 can be used as a starting point to develop a new class of drugs targeting JAK3 activity, and may have therapeutic potential in various diseases that are caused by aberrant JAK3 activity.
Department of Pediatrics, Division of Hematology/Oncology, New York Medical College, Valhalla, New York 10595, USA.
Byung-Hak
BH
Kim
Jun-Goo
JG
Jee
Chang-Hong
CH
Yin
Claudio
C
Sandoval
Somasundaram
S
Jayabose
Daisuke
D
Kitamura
Erika A
EA
Bach
Gyeong-Hun
GH
Baeg
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*; D014584:User-Computer Interface
C549326:10,13-dimethyl-17-(2-(6-sulfanylidene-3H-purin-9-yl)acetyl)-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta(a)phenanthren-3-one; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011687:Purines; D050799:STAT5 Transcription Factor; D054852:Small Molecule Libraries; D053616:Janus Kinase 3