Metastatic breast cancer cells show over expression of Tropomyosin receptor kinase C (TrkC) on cell surface, and this plays an important role in the proliferation of cancerous cells. Maytansinoids can disrupt microtubule function, thus inhibit cell division and proliferation. They are extremely toxic to cancerous cells, but due to their limited therapeutic window, their application is limited to warheads in many antibody-drug conjugates, where lower doses can deliver enhanced therapeutic effects relative to the free drug. Small molecule targeting has many advantages over antibody targeting strategy, such as better cell permeability, longer shelf life, and higher production efficiency. Yet very few small-molecule conjugates have been explored, and none that target the TrkC receptor. Previously, a small-molecule which binds preferably to TrkC was discovered in our group. This small-molecule targeting fragment was conjugated a maytansinoid via a cleavable linker; the conjugate shows improved therapeutic index in treating metastatic breast cancer cells.

Cleavable, targeted small-molecule maytansinoid conjugate improves therapeutic index on treating metastatic breast cancer

255th National Meeting (2018)

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