Oncology, Immunology, Inflammation, Virology
Treating Resistant Cancer with Stapled Peptide PROTACs
2022 Harrington Scholar-Innovator
A new weapon to fight acute myeloid leukemia (AML), and other relapsed and refractory cancers in children and adults, turns the enemy—cancer— against itself. The therapeutic approach uses a 3-in-1 modality, deploying a stapled (reinforced) p53 peptide proteolysis-targeting chimera (SP-PROTAC).
As guardian of the genome, p53 protects our cells from becoming cancerous. However, cancer can deploy its HDM2 and HDMX proteins to suppress p53 and activate oncogenic transcription by hijacking BET proteins. The Walensky lab designed a stapled p53 peptide linked to a small molecule BET inhibitor to synergistically degrade BET proteins and maximally reactivate p53 pathway by targeting HDM2 and HDMX. Blocking multiple oncogenic signaling pathways at once causes cancer to self-destruct.
“We hijack HDM2—the cancer cell's degrader of p53—and divert its attention to destroy cancer-causing proteins instead,” Dr. Walensky explains. “We simultaneously liberate p53 to resume its powerful tumor suppressor function.”
A chemical biologist and pediatric oncologist who cares for children with leukemia, Dr. Walensky knows the challenges associated with cancer relapse and its treatment. “We are laser-focused on achieving the benefits of multiagent therapy while minimizing the side-effects,” Dr. Walensky says. “We pack the biggest punch by targeting multiple cancer-causing pathways in the same cell at the same time, while also streamlining the clinical development path by advancing a single agent that does the job of three. Our Harrington advisors are an enormous asset—their insights and advice have been instrumental in helping us realize the full potential of our new drug modality.”