Jun J. Yang Ph.D., vice-chair of Pharmacy and Pharmaceutical Sciences, and Zoran Rankovic, Ph.D., director of St. Jude CBT Chemistry Centers.
More-effective therapies are greatly needed for children with the high-risk blood cancer T-cell acute lymphoblastic leukemia (T-ALL). St. Jude Children’s Research Hospital scientists have leveraged the latest chemical technology called a proteolysis targeting chimera (PROTAC) to develop a drug for these patients. The findings were published today in Science Translational Medicine.
Previous research led by co-corresponding author Jun J. Yang, Ph.D., St. Jude Departments of Pharmacy and Pharmaceutical Sciences and Oncology, revealed that the protein LCK is an important drug target in 44% of children with T-ALL. That work, published in Nature Cancer in 2021, demonstrated the feasibility of therapeutically targeting LCK using the common chemotherapy drug dasatinib. Unfortunately, small-molecule inhibitors such as dasatinib have two important weaknesses: They usually only block the target temporarily, and cancer cells mutate to circumvent the drug’s specific effect.
“Designing small-molecule inhibitors of a protein is like jamming a lock with a key,” Yang said. “It works well when it stays exactly right, but if the drug comes off, the protein will resume its normal function. The PROTAC approach is different. Rather than block the protein target, you’ve blown it up so that it isn’t there anymore and will never come back.”
PROTACs: a different approach to targeted therapy
Rather than blocking a target protein, PROTACs induce the degradation of a target, thereby eliminating it. They work through a targeting mechanism that brings the protein, in this case LCK, close to E3 ubiquitin ligase, which then marks it for destruction by the cell’s natural machinery for disposing of unneeded proteins.
Co-corresponding author Zoran Rankovic, Ph.D., St. Jude Department of Chemical Biology & Therapeutics, used a novel E3 ligase-directing motif called phenyl glutarimide to develop the St. Jude LCK-PROTAC SJ11646. This motif proved to be superior to other E3-directing molecules commonly used in PROTAC design. The researchers previously published the development of phenyl glutarimide in Angewandte Chemie.
A new therapy for T-ALL
Yang, Rankovic and their colleagues showed that SJ11646 was highly effective at eliminating the LCK protein and killing LCK-activated T-ALL. Pharmacokinetic and pharmacodynamic profiling found that SJ11646 improved the duration of LCK signaling suppression by 630% compared to dasatinib in patient-derived xenograft models of T-ALL. This improvement translated into extended survival in mouse models of leukemia.
The study provides pre-clinical proof of principle for the LCK-targeted PROTAC approach as a possible treatment for T-ALL. The researchers are also now testing SJ11646 in hundreds of other cancer models. Their work provides a blueprint for developing additional degradation-based therapeutics.
“Targeted protein degradation is a novel chemical biology paradigm with great promise for drug discovery,” Rankovic said. “While it still needs to be optimized for use as a leukemia therapy, we have a strong pre-clinical proof of principle demonstrating the feasibility of this approach.”
Authors, funding and technology
The study’s co-first authors are Jianzhong Hu and Jamie Jarusiewicz of St. Jude. The additional authors are David Teachey, University of Pennsylvania; and Guoqing Du, Gisele Nishiguchi, Satosh Yoshimura, John Panetta, Zhenhua li, Jaeki Min, Lei Yang, Divyabharathi Chepyala, Marisa Actis, Noemi Reyes, Brandon Smart and Ching-Hon Pui of St. Jude.
The study was supported by grants from the National Institutes of Health (R01CA264837, U01CA264610 and P30CA21765) and ALSAC, the fundraising and awareness organization of St. Jude.
If you are interested in partnering with St. Jude to further develop this or other PROTAC technologies, contact Chad Riggs, St. Jude Office of Technology Licensing.
Other PROTACs which are available for license include:
- Human G1 To S Phase Transition Protein 1 Homolog (GSPT1) Degrader (SJ-21-0001)
- JAK PROTAC (SJ-19-0047)
- New JAK PROTACs (SJ-21-0010)
- Proteolytic Targeting Chimeras (PROTACs) for Targeting LCK-driven Leukemia (SJ-21-0047)
- Small molecules that can be used for targeted protein degradation of CK1alpha, IKZF1 and IKZF3 (SJ-21-0048)
- Small molecules that can be used for targeted protein degradation of GSPT1/IKZF1 (SJ-21-0045)
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.