Carmot Therapeutics

Chemotype Evolution is a fast, empirical screening technology for discovering new high-affinity ligands. The process is target agnostic, compatible with almost any assay, and does not require structural information. Chemotype Evolution is valuable for converting fragments into leads, identifying new chemotypes, and expanding intellectual property.

Industry challenge

Currently, the discovery of new drugs relies heavily on high throughput screening (HTS) of chemical libraries that contain up to a few million molecules. Although successful for some disease targets, HTS works less effectively with new targets and with so-called “hard” targets. This failure is partly due to the fact that a million-molecule library represents a tiny sliver of relevant chemical diversity. Moreover, HTS collections contain compounds from past discovery programs and thus reflect the chemistry of old targets rather than current needs. Over the past decade, fragment-based ligand discovery has been embraced by many companies as an attractive complement to HTS. However, advancing fragments to leads remains a significant challenge. Chemotype Evolution offers a powerful solution to advance fragments to leads.

Chemotype Evolution

Chemotype Evolution rapidly expands low-affinity fragments into potent and diverse leads, thereby reducing cost and timelines. The process starts by selecting an anchor fragment or “bait” that interacts with the target of interest. A bait can be derived from known inhibitors, substrates, co-factors, peptide ligands or previously discovered fragments (see Figure). In addition to its affinity for the target, the bait contains a reactive functionality so that it reacts efficiently with Carmot’s proprietary fragments. This generates a custom library of two-component molecules biased towards the target of interest, which can be fed into any assay to identify productive bait-fragment combinations. These combinations contain the original bait and a companion fragment that contributes to the binding affinity of the linked molecule. Newly identified fragments can be repurposed as baits in a second screening cycle producing novel high-affinity hits. Several cycles of bait selection, linking and screening can be performed to evolve lead compounds toward the desired properties. This iterative screening paradigm provides experimental access to novel chemical diversity space.

Thus, Carmot offers an efficient, empirical solution to a persistent challenge in lead generation: how to advance promising fragments to leads. A screening campaign consisting of 3-5 screening cycles can be completed in 5-9 months, greatly accelerating the timeline from fragment to early lead. 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 leads. These leads can be further evolved through iterative cycles of linking and screening in order to identify compounds with the desired properties.

Applications of Chemotype Evolution

Chemotype Evolution has identified inhibitors of kinases as well as protein-protein interactions, and can be applied to a broad variety of targets. The process of Chemotype Evolution is assay-agnostic and, unlike most other fragment approaches, Chemotype Evolution can be conducted using large proteins, protein complexes, partially pure fractions of cell extracts, or even whole cells. Moreover, no structural information about the protein target is required.

Partnering opportunities

Carmot is currently seeking partners interested in applying Chemotype Evolution to high-value targets. Please contact us for further information at info@carmot.us