Can targeted degradation of LCK protein become a new strategy for treating T-cell acute lymphoblastic leukemia?

1. What are the therapeutic challenges of T-cell acute lymphoblastic leukemia (T-ALL)?

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most common hematologic malignancies in children. Compared to B-cell acute lymphoblastic leukemia (B-ALL), which has a relatively better prognosis, T-ALL patients typically present with more acute onset, stronger invasiveness, and lower response rates to conventional chemotherapy regimens. Although the overall survival rate of T-ALL has improved in recent years through optimized multi-drug combination chemotherapy and supportive care, the prognosis for relapsed/refractory patients remains poor. More critically, immunotherapies (such as CAR-T therapy), which have achieved revolutionary breakthroughs in B-ALL, face unique challenges in T-ALL, including the source of autologous T cells, potential on-target/off-tumor effects, and severe immunosuppression, and have not yet been fully matured. Therefore, developing novel targeted drugs that can precisely target T-ALL malignant cells and overcome drug resistance has become an urgent need to break through current therapeutic bottlenecks.

2. Why is LCK kinase a potential key therapeutic target for T-ALL?

Lymphocyte-specific protein tyrosine kinase (LCK) is a key member of the Src family of kinases and plays an indispensable role in the initiation and amplification of T-cell receptor (TCR) signaling. Previous studies have found that approximately 44% of pediatric T-ALL patients exhibit abnormal phosphorylation and activation of LCK kinase, suggesting that aberrant LCK activation may be an important mechanism driving the development of T-ALL. Based on this discovery, the multi-target tyrosine kinase inhibitor dasatinib, due to its inhibitory activity against multiple kinases including LCK, has been tested in clinical trials for T-ALL treatment. Dasatinib reversibly occupies the ATP-binding pocket of LCK, inhibiting its kinase activity. However, traditional small-molecule kinase inhibitor therapies have inherent limitations: their inhibitory effects are reversible and transient, requiring maintenance of high blood concentrations; cancer cells can easily develop resistance through mechanisms such as target mutations, bypass activation, or drug efflux pumps, leading to disease relapse.

3. How does PROTAC technology revolutionize the targeting of LCK?

To overcome the limitations of traditional inhibitors, proteolysis-targeting chimera (PROTAC) technology provides a novel drug design paradigm. A PROTAC molecule is a bifunctional small molecule, with one end binding to the target protein (e.g., LCK) via a ligand and the other end linking to an E3 ubiquitin ligase (e.g., CRBN) through a connector chain. This structure brings the E3 ligase "close" to the target protein, catalyzing the polyubiquitination of the target protein, which is then recognized and completely degraded by the cellular proteasome system.

Based on this principle, researchers designed and synthesized the LCK-targeting PROTAC molecule SJ11646. Its design cleverly links dasatinib (as the "warhead" for LCK) via an optimized connector chain to a novel CRBN E3 ligase ligand, phenyl-glutarimide. Unlike dasatinib's mechanism of "temporarily blocking the gun barrel," SJ11646 acts like "directly blowing up the bunker," catalyzing the irreversible degradation of LCK protein and eliminating its function at the root. This "event-driven" catalytic mode allows a single PROTAC molecule to be recycled, potentially achieving more durable and efficient targeted inhibition and overcoming resistance caused by target protein overexpression or mutations.

4. What is the key application value of human LCK protein in related drug development?

Throughout the design, screening, and mechanistic validation of PROTAC molecules, high-purity, high-activity human LCK protein is an indispensable core tool material, with applications spanning the entire process:

1. Binding affinity determination and structural optimization: In the early stages of PROTAC molecule design, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), or fluorescence polarization-based competitive binding assays are needed to precisely measure the affinity (KD value) of the "warhead" molecule (e.g., dasatinib derivatives) for human LCK protein, providing critical data for connector chain selection and overall molecule optimization.

2. In vitro validation of degradation efficiency: Before cell experiments, purified human LCK protein, PROTAC molecules, E3 ligase complexes, and proteasome components can be added to cell lysates or cell-free systems to establish an in vitro degradation system, enabling rapid, quantitative evaluation of the efficiency of different PROTAC molecules in inducing LCK ubiquitination and degradation for high-throughput preliminary screening.

3. Mechanistic studies and selectivity assessment: Human LCK protein can be used for in-depth biochemical mechanistic studies, such as validating the stability of the "target protein-PROTAC-E3 ligase" ternary complex induced by PROTAC molecules. Simultaneously, binding or competition experiments with protein panels containing other kinases (e.g., ABL, SRC family members) can assess the target selectivity profile of PROTAC molecules and predict potential off-target effects.

4. Drug activity and resistance mechanism exploration: By introducing site-specific mutations into human LCK protein (simulating clinically possible resistance mutations), it can be evaluated whether PROTAC molecules can still effectively bind and degrade mutant LCK, thereby prospectively studying their potential to overcome specific resistance mutations.

5. How does PROTAC SJ11646 perform in preclinical studies?

Preclinical study data fully demonstrate the superiority of the LCK-targeting PROTAC strategy. In T-ALL cell lines, SJ11646 can efficiently and rapidly induce LCK protein degradation, followed by massive apoptosis of leukemia cells. In mouse T-ALL xenograft models, SJ11646 exhibits stronger and more durable antitumor effects than dasatinib: after a single dose, its inhibition of LCK and downstream signaling blockade can last up to 72 hours, far exceeding dasatinib's less than 12 hours. In multiple T-ALL mouse models with different genetic backgrounds, SJ11646 significantly inhibits tumor growth, with some mice even achieving complete remission through single-agent treatment. Additionally, studies found that SJ11646 has multi-kinase degradation capabilities, simultaneously degrading other tumor-related kinases such as ABL, SRC, and KIT, which expands its potential applications in a broader range of tumor types. Preliminary in vitro safety assessments show low toxicity to normal cells, but specific mechanisms require further elucidation.

6. Which manufacturers provide human LCK protein?

Hangzhou Starter Biotechnology Co., Ltd. has independently developed "Human LCK Protein (His-tag)" (product name: Human LCK, His tag, catalog number: S0A6011), a key T-cell signaling kinase with high bioactivity, high purity, and excellent stability. This product is recombinantly expressed in mammalian systems with a C-terminal His tag and holds critical application value in immune research areas such as T-cell activation mechanism studies, immune receptor signal reconstruction, and drug screening.

Professional technical support: We provide detailed product technical documentation, including complete purity analysis reports, kinase activity validation data, recommended reaction buffers and substrate combinations, standard kinase assay protocols, and professional technical consultation, fully supporting customers in advancing immune signaling and drug development research.

Hangzhou Starter Biotechnology Co., Ltd. is committed to providing high-quality, high-value biological reagents and solutions for global innovative pharmaceutical companies and research institutions. For more details about "Human LCK Protein (His-tag)" (catalog number S0A6011) or to request sample testing, please contact us.

Product Information