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In the development of cancer therapeutics, molecular targeting approaches using small molecules have been successful. However, so-called "druggable" targets such as kinases have been exhausted–drug targets that can be tackled by simply inhibiting enzyme activity are running out year by year.
Under these circumstances, there are increasing expectations for inhibiting target functions by regulating protein-protein interactions (PPI).
However, at present, the acquisition of such PPI modulating-compounds is highly dependent on serendipity through random screening, and it is difficult to logically acquire compounds with a high probability of success.
In recent years, as represented by proteolysis targeting chimeras (PROTACs), it has become possible to change the function of target proteins by inducing proximity using bifunctional small molecules in which target protein A-binding compound and target protein B-binding compound are connected by a linker.
As a result, it has become possible to logically develop PPI-modulating compounds with a certain degree of accuracy, and expectations are high as a new technology that expands the target space for small molecule drug discovery.
We are looking for a methodology for rationally designing bifunctional small molecules that can inhibit target protein function through protein-protein interactions (PPI) based on protein structural information. (It does not matter whether the target interaction is intracellular or extracellular.) The types of molecules we want to design with this methodology are 1) Bifunctional molecules to redirect the interaction between target A and target B (type I) and 2) bifunctional molecules that inhibit target A by recruiting shield protein X (type II).
- Methodology for designing the above bifunctional molecules based on protein structure information
- A focused library of bifunctional small molecules useful for screening seeds for the above technologies
- An approach to convert inhibitory antibodies and peptides into small molecules. (Inhibitory antibodies or peptides are well-known success examples of PPI inhibitor though they are high- or middle-weight molecule. Attempts have been made to replace such molecules with small molecule compounds by using structure information, but no methodology has been established yet.)
- A specific example of a compound obtained by applying the methodology to some target must be included.
- Data showing the methodology is creating compounds with efficacy in vitro, using cultured cells. Efficacy means inhibiting the PPI of the target proteins and, as a result, inhibiting its function.
- Perform computational chemical design based on protein structure and obtain proximity-inducing bifunctional small molecule compounds.
- Methodology applicable to multiple targets (two or more targets)
- Oncology-related results such as growth inhibition in cancer cells are not required
- Approaches that rely on serendipitous identification, such as phenotype screening or cell-based screening
- Approaches that end with obtaining inhibitory antibodies or inhibitory peptides. The subsequent methodology for converting them into small molecules is important for us.
- Technologies to design inhibitors against a single target (not bifunctional). We are looking for methodologies that are useful for modulating PPI.
At Daiichi Sankyo, we attach significant importance to working with academic institutions, startups and bioventure companies to discover new therapeutics in the place where hypotheses are brought and tested in order to expand possibilities for scientific innovation breakthrough. We build sustainable relationships with partner institutions and companies through open and fair alliance management and trust based on mutual respect as the foundation for effective collaborations. Our goal is to jointly create new value for patients by maximizing each other’s expertise and strengths.
https://www.daiichisankyo.com/rd/strategy_operations/open_innovation/
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