Cyclopropyl-linked dipeptide tail improves oral PD-L1 small molecules
- A stereodefined cyclopropyl linker attaches polar groups to the solvent-exposed side of a biphenyl PD-L1 binder, allowing amino alcohols, amino acids, dipeptides and peptidomimetics to be compared.
- SAR pointed to a dipeptide-bearing (1S,2S) isomer as a strong blocker of the PD-1/PD-L1 interaction with clear PD-L1 binding.
- It showed better solubility, microsomal stability and oral exposure in mice, and orally dosed it slowed melanoma growth with immune activation and good tolerability.
💡 Points Based on the abstract
Putting the polar tail on a rigid cyclopropyl instead of a floppy chain is a smart way to pay the entropy bill, and the stereo-dependence of (1S,2S) hints the vector really matters. But biphenyl PD-L1 binders are known for inducing dimerization, so I'd want a crystal structure or at least a clear dimer assay, plus a human PD-L1 comparison, before trusting the mouse efficacy.