Last update 01 Nov 2024

HCK x LCK

Last update 01 Nov 2024

Basic Info

Related Targets

HCKLCK

Drugs associated with HCK x LCK

A-419259

Target

HCK x LCK

Mechanism

HCK inhibitors [+1]

Active Org.

Abbott Laboratories

Originator Org.

Abbott Laboratories (Philippines), Inc.

Active Indication-

Inactive Indication

Myeloid Leukemia

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HCK x LCK

100 Translational Medicine associated with HCK x LCK

0 Patents (Medical) associated with HCK x LCK

131

Literatures (Medical) associated with HCK x LCK

01 May 2024·Scandinavian Journal of Immunology

Interaction of T‐cell‐specific adapter protein with Src‐ and Tec‐family kinases

Article

Author: Huszenicza, Zsuzsa ; Spurkland, Anne ; Chan, Hanna ; Granum, Stine ; Sundvold, Vibeke ; Gilmour, Brian C. ; Kjelstrup, Hanna ; Koll, Lise

AbstractAdapter proteins are flexible and dynamic modulators of cellular signalling that are important for immune cell function. One of these, the T‐cell‐specific adapter protein (TSAd), interacts with the non‐receptor tyrosine kinases Src and Lck of the Src family kinases (SFKs) and Itk of the Tec family kinases (TFKs). Three tyrosine residues in the TSAd C‐terminus are phosphorylated by Lck and serve as docking sites for the Src homology 2 (SH2) domains of Src and Lck. The TSAd proline‐rich region (PRR) binds to the Src homology 3 (SH3) domains found in Lck, Src and Itk. Despite known interactors, the role TSAd plays in cellular signalling remains largely unknown. TSAd's ability to bind both SFKs and TFKs may point to its function as a general scaffold for both kinase families. Using GST‐pulldown as well as peptide array experiments, we found that both the SH2 and SH3 domains of the SFKs Fyn and Hck, as well as the TFKs Tec and Txk, interact with TSAd. This contrasts with Itk, which interacts with TSAd only through its SH3 domain. Although our analysis showed that TSAd is both co‐expressed and may interact with Fyn, we were unable to co‐precipitate Fyn with TSAd from Jurkat cells, as detected by Western blotting and affinity purification mass spectrometry. This may suggest that TSAd‐Fyn interaction in intact cells may be limited by other factors, such as the subcellular localization of the two molecules or the co‐expression of competing binding partners.

01 Jan 2024·Chemical Biology & Drug Design

Exploring antiproliferative activities and kinase profile of ortho‐substituted N‐(4‐(2‐(benzylamino)‐2‐oxoethyl)phenyl)benzamides

Article

Author: Khayat, Maan T ; Mass, Shaza A ; El-Araby, Moustafa E ; Malebari, Azizah M ; Omar, Abdelsattar M ; Muhammad, Yosra A ; Ahmed, Farid ; Elfaky, Mahmoud A ; Ibrahim, Sara M

AbstractDesigning kinase inhibitors that bind to the substrate site of oncogenic kinases in a promising, albeit less explored, approach to kinase inhibition as it was sought to avoid the issue of untoward off‐target modulations. Our previously identified compound KAC‐12 with a meta‐chlorophenyl substitution was an example of this approach. While it showed confirmed inhibitory activity against cancer cells, this substitution shifted the profile of affected targets away from Src/tubulin which were seen with the parent KX‐01. In this paper, we synthesized compounds with ortho‐substitutions, and we investigated the effect of such substitutions on their cellular and subcellular activities. The compound N‐(4‐(2‐(benzylamino)‐2‐oxoethyl)phenyl)‐2‐(morpholine‐4‐carbonyl)benzamide (4) exhibited substantial activities against cell lines such HCT116 (IC50 of 0.97 μM) and IC50 HL60 (2.84 μM). Kinase profiling showed that compound 4 trended consistently with KAC‐12 as it did not affect Src, but it had more impact on members of the Src family of kinases (SFK) such as Yes, Hck, Fyn, Lck, and Lyn. Both compounds exhibited profound downregulation effects on Erk1/2 but differed on others such as GSK3α/β and C‐Jun. Collectively, this study further support to the hypothesis that small structural changes might bring higher changes in their kinome profile.

01 Jun 2023·The American Journal of Pathology

NEF-Induced HIV-Associated Nephropathy Through HCK/LYN Tyrosine Kinases

Article

Author: Jolicoeur, Paul ; Bénichou, Serge ; Priceputu, Elena ; Bouchard, Nathalie ; Hanna, Zaher ; Chrobak, Pavel ; Cool, Marc ; Hu, Chunyan ; Lowell, Clifford A ; Royal, Virginie ; Forestier, Clara

HIV-1-associated nephropathy (HIVAN) is a severe complication of HIV-1 infection. To gain insight into the pathogenesis of kidney disease in the setting of HIV, a transgenic (Tg) mouse model [CD4C/HIV-negative regulator factor (Nef)] was used in which HIV-1 nef expression is under control of regulatory sequences (CD4C) of the human CD4 gene, thus allowing expression in target cells of the virus. These Tg mice develop a collapsing focal segmental glomerulosclerosis associated with microcystic dilatation, similar to human HIVAN. To identify kidney cells permissive to the CD4C promoter, CD4C reporter Tg lines were used. They showed preferential expression in glomeruli, mainly in mesangial cells. Breeding CD4C/HIV Tg mice on 10 different mouse backgrounds showed that HIVAN was modulated by host genetic factors. Studies of gene-deficient Tg mice revealed that the presence of B and T cells and that of several genes was dispensable for the development of HIVAN: those involved in apoptosis (Trp53, Tnfsf10, Tnf, Tnfrsf1b, and Bax), in immune cell recruitment (Ccl3, Ccl2, Ccr2, Ccr5, and Cx3cr1), in nitric oxide (NO) formation (Nos3 and Nos2), or in cell signaling (Fyn, Lck, and Hck/Fgr). However, deletion of Src partially and that of Hck/Lyn largely abrogated its development. These data suggest that Nef expression in mesangial cells through hematopoietic cell kinase (Hck)/Lck/Yes novel tyrosine kinase (Lyn) represents important cellular and molecular events for the development of HIVAN in these Tg mice.

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