Published in the journal Cell Chemical Biology, the study, "Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling," found that the molecular glue drug lenalidomide could restore the tumor immunotherapy effect of the PD-1 antibodyPD-1 antibody and inhibit tumor growth in mice lacking T-cell co-stimulatory signals. PD-1 is a checkpoint protein on T cells. It normally operates as a type of 'off switch' that helps keep T cells from attacking other cells in the body.
"Science-based innovation is core to Degron's exploration into the mechanisms of molecular glue drugs and cancer immunity. The work performed in Dr. Cang's lab reveals that degradation of IKZF1 and IKZF3, can reinvigorate T cells to attack cancers by modulating immune regulatory networks," said Lily Zou, Ph.D., co-founder and CEO of Degron. "This discovery provides new ideas for Degron to dial in such activities into our molecular glue programs when appropriate."
"Degron's pipeline of molecular glue degraders against novel oncology targets can be chemically modified to selectively retain the ability to degrade IKZF1 and IKZF3. As a result, such drugs can kill cancer cells by two different mechanisms, directly inactivating oncogenesis and by inducing T cells to target the cancer cells," said Dr. Cang.
Dr. Cang's team demonstrated that lenalidomide could co-stimulate T cells by upregulating the secretion of the immune system signaling molecule, interleukin-2 (IL2). Through transcriptome sequencing, the researchers found that lenalidomide can also upregulate Notch targets. Simultaneously blocking both IL2 and Notch signaling pathways simultaneously limits the co-stimulatory effect of lenalidomide on T cells, rendering the combination therapy of lenalidomide and PD-1 antibody ineffective.
The research was mainly supported by the National Natural Science Foundation of China, the Shanghai Science and Technology Commission, and ShanghaiTech University.
Degron Therapeutics is a biotechnology company advancing human health by developing novel medicines using its robust molecular glue-based targeted protein degradation drug discovery platform. The company's unique GlueXplorer® platform has created a rapidly expanding IP-protected compound library and screening system to develop a new class of small-molecule medicines that target previously undruggable disease targets. The company's pipeline includes a growing number of preclinical compounds for oncology, inflammation, metabolic disease, and rare diseases. For more information, please visit www.degrontx.com.
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