Today, protein degradation company Cedilla announced that it has acquired Thirdrock's $56.2 million Series A financing, which will use protein degradation technology to develop targeted non-medicinal protein drugs. Unlike other protein degradation companies that rely on the PROTAC technology platform, such as Arvinas and C4, Cedilla does not develop a general-purpose protein degradation technology. Instead, it selects regulatory points for degradation kinetics of different targets to reduce its stability, and is already present in cells. The degradation mechanism is found and degraded. So Cedilla will use small molecule drugs in the traditional sense, rather than PROTAC with a larger molecular weight and a poor PK. It is said that eight early projects are currently underway.
Drug source analysis
In the past two years, PROTAC has been the core of protein degradation technology. This technology has made breakthroughs in several frontiers such as target confirmation, oral absorption, crystal structure and selectivity improvement. However, PROTAC needs to bind to both the target protein and an E3 binding enzyme. However, the current technology mainly connects the two ligands into a PROTAC molecule by chemical chain, so it is bound to have large molecular weight, high flexibility, membrane and metabolic stability. face the challenge. Of course, because the catalytic degradation mechanism of PROTAC makes this obstacle smaller than traditional small molecule drugs, it is still a technical obstacle.
Cedilla does not disclose much information, but according to its website, the technology relies mainly on interference with protein stability control systems. Some small molecule drugs such as androgen receptor antagonists can induce degradation of the receptor, but this finding is accidental. Cedilla hopes to make this type of discovery more systematic, either directly binding to the protein or by interfering with the post-expression modification of the protein to reduce its stability. Another strategy is to interfere with the protein/protein complex required for the stable presence of the target protein in the body, so that the target protein becomes orphaning and is degraded by the degradation system. Of course, these technologies require evaluation system support. Cedilla claims to have a proteome stability evaluation system that can analyze the stability of a large number of proteins and its degradation mechanism.
Compared with PROTAC, the advantage of Cedilla is that it does not require a large bifunctional PROTAC. However, the disadvantage is that each target needs to study its stable mechanism separately and find the interfering substances through screening. This will be a time-consuming and labor-intensive mode. . Although theoretically only a catalytic amount of drug is needed, the kinetics are more complex and many details take time to study. One of the most attractive features of PROTAC is that selectivity can be improved to some extent because PROTAC, which binds to multiple similar proteins, typically only degrades part of the protein. This advantage will no longer exist in Cedilla technology.
Protein degradation technology emerges because most protein targets cannot be regulated by traditional small molecules or antibody drugs. The former is limited by selectivity and membrane cleavage, and the latter can only regulate extracellular targets. Although RNA technology has recently progressed rapidly, it is now only sufficient to show medicinal properties at individual targets. Cedilla's technology is similar to another indirect regulation of non-medicated protein technology, Warp Drive Bio's SMART, and SMART's growth history may be a benchmark for Cedilla. Recently, the discovery of small molecule drugs has entered a bottleneck period, and the emergence of these new technologies may revitalize this traditional pillar. (Source: Sina Pharmaceutical Network)
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