Acute lymphoblastic leukemia (ALL) is a common disease. B-ALL and T-ALL account for 85% and 15% of the two lymphatic lineages of ALL, respectively, but patients with T-ALL have poor life quality and short survival time. Although children with T-ALL have better therapeutic results than adults, they will suffer a series of side effects after long-term chemotherapy. Therefore, children with T-ALL urgently need more effective treatment.
Scientists from St. Jude Children’s Research Hospital developed an innovative drug for these children using the latest chemical technology of proteolytic targeted chimera (PROTAC) on Aug. 24. The study was published in Science Translational Medicine.
A study conducted in 2021 by the study’s co-author, Dr. Jun J. Yang, showed that LCK protein is an important target in children with 44%T-ALL, which can be blocked by dasatinib. However, like common chemotherapeutic drugs, tumor cells will mutate after long-term use to avoid the specific killing effect of the drugs.
“Designing small molecular inhibitors of proteins is like unlocking with a key,” Yang said, “it works well when the two matches perfectly. But once the drug falls off, the target protein will return to its normal function. The principle of PROTAC is different. Instead of blocking the target protein, you just blow it up and the target protein no longer exists. “
When designing the molecular structure of LCK PROTAC, the researchers used a new E3 ligase ligand, , and the data showed that the degradation effect of this compound was better than that of various common E3 ligase ligands.
When evaluating the LCK PROTAC, the team used KOPT-K1, a T-ALL cell line sensitive to dasatinib, as a model. The data showed that LCK was completely degraded within 24 hours by 100 nM of drugs, and the degree of LCK degradation was positively correlated with the cytotoxicity of KOPT-K1.
Compared with small molecular inhibitors, PROTAC can irreversibly degrade the target protein, and the action time should be longer in theory. After the KOPT-K1 cells were treated with LCK PROTAC and dasatinib for 18 h, the researchers found that the cells treated with dasatinib resumed growth after 96 h, while the growth inhibition time of cells treated with LCK PROTAC was as long as 240 h.
Pharmacokinetic and pharmacodynamic analysis showed that in the patient-derived T-ALL mouse xenotransplantation model, the signal inhibition of LCK PROTAC on LCK was 630% longer than that of dasatinib, and effectively prolonged the survival time of the model mice.
Since the inhibitory effect of LCK PROTAC on LCK is longer than that of dashatinib, it is expected that this property can be translated into a stronger anti-leukemia effect in vivo. The results showed that both dasatinib and LCK PROTAC could inhibit the growth of T-ALL, but the inhibitory ability of LCK was significantly better than that of dasatinib, and no safety risk was observed.
In summary, this study provides a preclinical proof of T-ALL treatment with PROTAC. Researchers are currently testing the effectiveness of the drug in hundreds of other tumor models. “Targeted protein degradation is a new biological paradigm with great potential in the field of drug discovery,” Rankovic said, “l though this drug needs to be further developed for the treatment of leukemia, our strong preclinical proof of concept has proven the effectiveness of this approach. “