Carmot is pioneering a transformative drug discovery approach, Chemotype Evolution, to identify superior therapeutics for human diseases. Chemotype Evolution is a proprietary technology that dramatically expands the repertoire of chemical diversity for drug discovery. The approach is target-agnostic and rapidly accesses novel and target-relevant chemical diversity, providing the opportunity to tackle therapeutic targets refractory to traditional approaches. Carmot is using Chemotype Evolution to identify and optimize innovative drugs for challenging targets, thereby addressing important unmet chemical needs.
Discovering novel small molecule leads for drug development depends on the ability to efficiently search chemical diversity. High-throughput screening (HTS) has delivered many new leads, but even the largest HTS collections pale in comparison with chemical diversity space. HTS fails to produce attractive hits for roughly half of new targets, in part because HTS collections lack suitable compounds for the targets of interest. Chemotype Evolution offers an alternative approach by providing rapid access to novel chemical diversity that is tailored to the target of interest.
Using Chemotype Evolution, Carmot can generate potent, nascent leads from a variety of starting points. The process starts by selecting an anchor molecule or “bait” that interacts with the target of interest (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. To identify productive bait-fragment combinations, the customized library is screened against the target in assays that detect binding or modulation of target activity. 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 can be 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, bottom).
Figure. Schematic representing three iterations of Chemotype Evolution to transform a low-affinity molecule (Bait A, IC50>100 micromolar) into a potent starting point for lead optimization. In each iteration, one or more baits are individually coupled to 5,000-7000 fragments to generate a custom-made compound library that can be screened in any plate-based assay. Hits are validated in subsequent assays and compounds with desired properties are identified. 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 a highly efficient process: it is possible to synthesize and screen tens of thousands of compounds per iteration. The process is assay-agnostic and can be guided by numerous selection methods including inhibition, activation, or ligand binding assays. Screens can be conducted using large or impure proteins, protein complexes, and even cells. Significantly, the technique does not require structural information about the protein target. Carmot employs several coupling chemistries and the resulting compounds contain either no linkers, short rigid linkers, or short flexible linkers that can be easily replaced to generate ever more potent hits. 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.
By combining validated baits with Carmot’s fragment collection, Chemotype Evolution provides access to vast and target-relevant chemical diversity with efficiency unmatched by other techniques. Unlike traditional HTS, where a static library is screened once against a given target, each cycle of Chemotype Evolution creates a new chemical library that can generate multiple chemical series, each of which can be further evolved through additional screening iterations. By progressively assembling three-fragment molecules, Chemotype Evolution can access a chemical diversity space exceeding 300 billion compounds (7,0003). The target-directed bait ensures that the process focuses on target-relevant chemical diversity. The linking chemistry enables rapid generation of novel compounds without the need for purification and is much faster than traditional anchor libraries. Using Chemotype Evolution, Carmot can advance high micromolar starting points to submicromolar leads in a few months.
Applications of Chemotype Evolution
Chemotype Evolution has identified nanomolar inhibitors of kinases and protein-protein interactions starting from molecules with mid- to high micromolar 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. In this scenario, bait A in Figure 1 is a peptide fragment that interacts with the target. The peptide fragment is kept during the first two iterations (baits A and B) to provide potency and target specificity, but is replaced during the third iteration (bait D) to generate a non-peptidic small molecule. 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 at email@example.com