FIMECS
Drugging Undruggable Targets

While biotech and pharma companies have developed significant breakthroughs for numerous chronic diseases, yet there are multiple targets in the immuno-oncology and oncology space that are currently undruggable. There have been over 1,500 proteins reported as being pathogenic or potentially related to certain diseases. However, only 300 of them are druggable by conventional medicines (e.g., small molecule, antibody).Targeted protein degrader has very high potential to modulate the function of the other 1,200 target proteins. Also, because of the mechanism of this innovative modality, protein degradation drugs are expected to show great efficacy at a much lower dose and higher selectivity to the target, thus lower toxicity. FIMECS is a biotech firm developing a new class of drugs based on targeted protein degradation for the currently ‘undruggable’ targets in immuno-oncology and oncology areas. “Our targeted protein degradation technology can degrade disease-relevant proteins directly making it applicable to “undruggable” targeted proteins with conventional modalities,” states Yusuke Tominari, Ph.D. CEO, CSO, and co-founder, of FIMECS.

He sheds light on the current protein degradation activity used in the process of drug discovery that does not correlate with binding affinities of each target protein and E3 ligase. The most important thing is the cooperativity of the ternary complex by protein-protein interaction for the efficient ubiquitin transfer. However, the prediction of cooperativity is quite limited in the silico calculation. The best E3 ligase varies based on the target protein, and the drug-like property is generally poor due to mid-size molecules. On the other hand, FIMECS’ solution, RaPPIDS includes two steps, which are the lead generation stage and optimization stage for protein degradation. For the purpose of lead generation, FIMECS has prepared and stocked “Ready to conjugate probe library” containing proprietary E3 binders in order to quickly prepare 20~50 compounds by conjugating with the probe library to target protein binders. After identification of the best E3 ligase binder and appropriate linker length for the target protein, FIMECS moves to the next step for the lead optimization. Here, a large number of divergent degraders are rapidly generated by semi-automated synthesis based on fragmented linkers and E3 binders.

In addition, FIMECS is currently focusing on developing pseudokinase degraders. “Pseudokinase is catalytically inactive due to changes in motifs that are essential for kinase activity; therefore, it is difficult to modulate its function by conventional small molecules. Combining with degrader modality allows us to generate fundamentally new medicines for targeting this kind of target class,” says Tominari. The company is working on pseudokinases, IRAK-M and TRIB1, for immuno-oncology and haematological oncology area targeted by degrader molecules. In fact, its first program, IRAK-M degrader, is under pre-clinical toxicological studies.

With rapid and diversity-oriented synthesis and evaluation, FIMECS has the experience to deliver drug candidate within a year after identification of a lead degrader. It can be used not only for internal programs but also for collaborative programs. Additionally, having a number of applicable E3 ligase binders are one of the strong points in the market because the alternative options can be provided based on targets. Internally, the FIMECS team has experienced in several cases that its proprietary E3 binders work successfully to degrade desired target proteins despite the failure of molecules combined with the binders of well-known E3 ligase like CRBN and VHL.FIMECS can provide the same opportunity to its clients. “Although there is no E3 ligase to be universally used, we can contribute to achieve quick drug discovery success with the continuous expansion of E3 ligase binder line-up and our platform technologies,” says Tominari. FIMECS has proprietary XIAP binders with different pharmacophore from the traditional IAP binders, SMAC mimetics. The company is now pursuing the novel E3 ligase binders which are applicable for degrader modality.

What further differentiates FIMECS is the fact that it has proprietary First-in-Class programs in particular pseudokinases. For example, the most advanced program, IRAK-M degrader, which is in the pre-clinical stage, has an important role in tightly controlling innate immune responsiveness to preserve homeostasis, mediating immune tolerance, and acts as a negative feedback regulator of TLR/IL-1R signaling pathway. Targeting IRAK-M, which expression is restricted to myeloid cells, would be potentially limiting adverse events against non-target tissues. “From supporting evidence for the role of IRAK-M in the innate immunosuppressive capacity of myeloid cells, we have developed compounds targeting IRAK-M as an effective cancer-immunotherapy strategy,” mentions Kanae Gamo, Vice President Biology and co-founder, of FIMECS. Further, the IRAK-M program for immune-oncology uses Target Product Profile(TPP) is an injected administration (e.g., i.v. or s.c.) to strictly manage Pharmacokinetics (PK) to decrease the on-target toxicity risk. However, TPP of the conventional oncoprotein targets might be oral administration. FIMECS is challenging the current status quo by developing the oral available degraders based on proprietary small molecular weight binders in its upcoming program. And the various processes are summarized in RaPPIDS, which can prepare and evaluate many kinds of non-bias designed degrader molecules selecting the best compound based on actual data including degradation activity and drug-like property such as cellular permeability, metabolic stability, and PK.

Among the FIMECS’ recent releases are the launch of cocktail synthesis and evaluation system, as an application of RaPPIDS that can rapidly prepare more than 100,000 degraders as a mixture. The company has also established the system for evaluation cell permeability of mixture of degraders with high sensitivity in collaboration with Axcelead Drug Discovery Partners, Inc. (Kanagawa, Japan). FIMECS can select the promising molecules with better permeability which should be re-synthesized by RaPPIDS.

To simplify the process of drug target identification and validation for degrader modality, FIMECS has been collaborating with Prof. Kanemaki at National Institute of Genetics(Shizuoka, Japan). He has established in vitro Auxin Inducible Degron (AID) technology, which can directly confirm the phenotype based on targeted protein degradation of a degron-fused protein of interest. The collaborative work is to expand in vivo application of AID that will allow FIMECS to prioritize target protein by AID technology in the near future. Finally, FIMECS’ roadmap also includes the expansion of E3 ligase line-up to address many kinds of proteins in collaboration with Academia focusing on tissue-specific E3 ligase.