Carmot Therapeutics, Inc. is pioneering a transformative drug discovery approach, Chemotype Evolution, to identify superior therapeutics. Chemotype Evolution is a proprietary technology that dramatically expands the repertoire of chemical diversity for drug discovery. The approach rapidly accesses novel, target-relevant chemical diversity to tackle therapeutic targets refractory to traditional approaches. Carmot is using Chemotype Evolution to identify and optimize innovative drugs for challenging therapeutic targets, thereby addressing important unmet chemical needs.
Discovering novel small molecule drug leads depends on the ability to efficiently search chemical diversity. High-throughput screening (HTS) has delivered many new leads, but fails to produce attractive hits for roughly half of new targets. Chemotype Evolution offers an alternative approach by providing rapid access to novel chemical diversity that is tailored to the target of interest. Chemotype Evolution can generate small molecules, peptides, or small molecule-peptide hybrids.
Using Chemotype Evolution, Carmot can generate potent leads from a variety of starting points. The process starts by designing an anchor molecule or “bait” (see Bait A in Figure). The bait can be derived from known inhibitors, substrates, co-factors, peptides or hits from a fragment screen. In addition to its target-interacting components, the bait contains a reactive functionality (“X” in Figure) such that it can be linked individually with every member of Carmot’s fragment collection. The linked molecules constitute a custom library of two-component molecules biased towards the target. This customized library is screened against the target to detect binding or modulation of target activity in biochemical or cell-based assays. Importantly, Chemotype Evolution does not screen pools of compounds; all compounds are synthesized and tested individually.
Hits identified from a first iteration screen can be fed into a medicinal chemistry program or converted into new baits (Bait B, center left in Figure) and used in a second iteration screen to identify more potent molecules. Alternatively, fragment hits can be repurposed as baits (Bait C) to identify fragments that replace the initial anchor molecule. This process can be repeated multiple times if desired (Figure, last row).
Figure. Three iterations of Chemotype Evolution to transform a low-affinity molecule (Bait A,IC50>100 micromolar) into a potent drug lead. In each iteration, one or more baits are individually coupled to up to 8000 fragments to generate a custom-made compound library that can be screened in any plate-based assay. The first iteration creates a hybrid molecule that contains the original bait. This molecule can be used as a bait in a second iteration (Bait B) to further increase potency and/or other desirable properties. Alternatively, the second iteration (Bait C) can be used to create a new molecule that is completely different from the original chemotype. A third iteration can be used to evolve a novel three-fragment molecule that lacks the original bait. At any point, compounds can be taken into lead optimization.
Chemotype Evolution is highly efficient, with tens of thousands of molecules screened per iteration. The process does not require compound purification and typically two baits or up 16,000 novel compounds can be generated and screened per target per month. Importantly, the technique does not require protein structural information. Carmot’s fragment collection has been custom-built for the technology over several years focusing on diversity, lead-likeness, and low molecular weight and lipophilicity.
Applications of Chemotype Evolution
Chemotype Evolution has identified nanomolar inhibitors of kinases and protein-protein interactions starting from molecules with micromolar to millimolar potency. Importantly, Chemotype Evolution can also be used to transform peptides into small molecules by using peptides or peptide fragments as starting points. Carmot is applying this approach to generate novel ligands for GPCRs and inhibitors of protein-protein interactions. Chemotype Evolution thus provides an efficient and systematic approach for converting peptides into small molecules, a goal that has remained a significant challenge in drug discovery.
Carmot is seeking to work with partners interested in applying Chemotype Evolution to high-value targets of mutual interest. Please contact us for further information.