The PPKM class holds promise for addressing several unmet needs in medicine, yet it is under-utilized because the highly complex structures of PPKMs impede chemical synthesis and are the main challenges for development. For PPKMs to reach their potential, improved chemistries with improved yields and stereospecificity that are also fast and economic are required to successfully identify high impact compounds for further development. Feasible total synthesis will accelerate optimizing such compounds for better drug-like properties.
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One set of polypropionate precursors that can be easily produced by the CCC on a large scale.
We are designing molecules with polypropionate polyketide macrolide (PPKM) scaffolds. PPKMs tend to be large in molecular size, complex in structure with multiple chiral centers and do not comply with the Lipinski’s rule-of-five, but they tend to have strikingly well-balanced conformational pre-organization and flexibility. They bind to protein targets with little loss of entropy and can be easily designed to be bioavailable because of their flexibility of adopting different conformations in aqueous and lipophilic environments. The large size and complex structure of polyketides make them especially suitable for traditionally difficult targets, such as PPI (protein-protein interaction) modulations.
We developed the Chiral Carbon Catalog (CCC) synthesis platform; a synthetic toolbox that allows large scale economic and fast synthesis of various complex PPKM building blocks/precursors from simple starting materials. This ensures adequate supply of those building blocks for the development of complex chiral PPKM for drug development.
THE CHIRAL CARBON CATALOG (CCC)
Two of the major classes for cancer treatment are macromolecules (e.g. antibodies) and small molecules (e.g. chemotherapy). Antibodies have great affinities and specificities for their target proteins. On the contrary, small molecules have low affinity for their targets but great permeability and better pharmacokinetic (PK) properties. There is a need to design small molecules that combine the affinities/specificities of antibodies and the permeability of small molecules to serve as ideal starting points for drug discovery. PPI (protein-protein interaction) modulation is the mechanism by which antibodies operate, and it is the reason for their high affinity and specificity.