Today Kronos, a small molecular microarray (SMM) company led by Geely CSO, announced a $105 million round of support. In addition to Vida, Omega and other VC companies, investors also include the personal investment of former Geely CEO Martin and former Kite CEO Belldegrun, who was acquired by Geely for $12 billion. Kronos's SMM platform is said to be able to find small ligands for traditional drug targets such as transcription factors, coenzymes, protein/protein, protein/DNA interactions and so on. The two most mature products of Kronos are MARC and CDK9.
SMM was invented by Schreiber in the 1990s. Angela Koehler, the founder of Kronos and professor of MIT, was one of Schreiber's students. At the peak of solid-phase combinatorial chemistry, they invented a technology to disperse each resin ball into microcapsules, then cut off the compounds synthesized by combinatorial chemistry on each resin ball and connect them to a chemically modified glass surface via covalent bonds or hydrophobic non-covalent bonds. Target proteins or cell lysates can be poured onto the surface covered by a large number of different small molecule compounds. After washing, fluorescent labeled antibodies can be used to detect which proteins bind to which compounds.
This screening model is different from another ultra-high throughput, binding-centric (only binding, not necessarily functional consequences) screening technology DEL. Del technology requires that proteins and compounds should be modified to a certain extent. The protein is attached to the stationary phase, so it may affect the conformation of the binding region of the protein. Small molecules need to be labeled with DNA coding, which may also affect the binding of proteins. SMM only needs to label small molecules, and proteins are natural proteins if they do not need special antigen labels. If cell lysate proteins are used, they may also preserve various binding partners in the cell environment, so they are closer to the original state of the target in the cell, which is the greatest advantage of SMM platform. Small molecules can not only be micro-printed on the glass surface, but also have the technology to connect a single small molecule to a single DNA molecule and really screen targets at the molecular level.
SMM has some advantages in maintaining the original protein ecology, but the scale of compound pool is far lower than DEL. Although DEL is hot, except RIP1, it does not significantly improve the drug-forming properties of non-proprietary drug targets. In addition, regardless of the screening technology, whether we can find high-quality pioneers or not depends more on the quality of the compound library. Although SMM has no restriction on DNA compatibility of DEL, the diversity of frameworks in combinatorial chemical synthesis libraries is limited. Whether this technology can significantly improve the success rate of non-proprietary drug targets remains to be confirmed. Recently, another large-scale screening technique for protein ligands in cell environment is Cravatt's Full Functionalized Fragment (FFF) technique, in which 176 active ligands were found with only 8 enantiomers. This technology is most likely to find new skeleton ligands for difficult drug targets.
Both DEL and SMM use binding force as evaluation criteria, and binding with proteins is the first step for small molecules to affect protein function. Compound-protein binding may have many effects on protein function. Traditional small-molecule drugs, regardless of orthomorphism, inhibit or activate the catalytic or signal transduction function of proteins. Such drugs can also be identified as purified proteins. However, the binding of proteins to small molecules may also affect their stability in cells and the ability to form natural complexes with other proteins. Such drugs can only be found in the cell environment, and can not be screened with purified proteins. Schreiber, the inventor of SMM, recently proposed a new model for finding these drugs, which is estimated to be due to the dimerization of various proteins triggered by SMM and earlier FK506. Even if the ligand just falls into the random binding chamber of the protein and has no effect on the function of the protein, the degradation of the protein can now be induced by PROTAC technology. Kronos also developed PROTAC drugs, but focused on the new direction of tumor-specific expression of E3-linked enzymes. In addition to the regulation of these protein levels, ASO, RNAi and small molecule RNA splicing inhibitors are also a force that can not be ignored. The days of impunity for targets that are not ready for medication will not be long.