Ubix Therapeutics develops PROTAC-based New Immuno-Anticancer Agent
입력 2018-11-12 09:40 수정 2018-11-12 09:40
by Euna Lee
Ubix Therapeutics, founded in June 2018, is currently promoting the commercialization of PROTAC for the first time among domestic companies, by introducing “Degraducer Technology”, the “PROTAC Technology” developed by the Korea Research Institute of Chemical Technology and the Korea Research Institute of Bioscience and Biotechnology through a Creative Convergence Research Project that is supported by the National Research Council of Science & Technology. In particular, the company is concentrating on the development of new drug targeting the epigenetics and new immune-checkpoint proteins. The company recently moved into the Seoul BioHub located in Hongreung, Seoul.
Seo Bo-gwang, the president of Ubix Therapeutics, said, “PROTAC is a strong technology for inhibitors that are capable of targeting the diseases that had been undruggable so far, and this technology is being spotlighted in the global market”, “The competitiveness of Ubix Therapeutics is based on the secured diversity of the PROTAC platform, which consists of ‘Target Ligand - Linker - E3 Ligase Binder’.”
President Seo graduated from the Dept. of Microbiology, Seoul National University, and his career has included work in JW Pharmaceuticals, Genexine, the In Vitro Diagnosis Division of SK Telecom, and Lifecore Partners; the experiences therein have became the foundation of this new startup in the Bio-pharmaceutical industry.
◇ The ‘PROTAC’ technology enables Degradation of Disease causing Proteins – what is the strong point?
Proteolysis Targeting Chimera (PROTAC) is a product resulting from target inhibition technology that exploits the ‘ubiquitin-proteasome system (UPS)’ to degrade the target protein of disease, instead of misfolded protein. The PROTAC consisting of ‘Target ligand – linker – E3 ligase binder’ efficiently combines with E3 ligase, the core element of UPS, and simultaneously with the target protein. It invokes E3 ligase to come to the target protein causing disease, and induces degradation by attaching ubiquitin signal. This is an approach that differs from that of conventional drugs, by disturbing the functions of target proteins causing disease, through exploiting the mass binding in the drug pocket of target proteins.
PROTAC holds the advantages of traditional small molecule compounds, and enables recycling in the process of proteolysis and low-dose administration, without the need to inhibit the drug pocket of target with high dose. This is why PROTAC is expected to render excellent therapeutic consequences with less side effects, compared with existing cytotoxic therapeutics. It offers the possibility of overcoming the tolerance against anticancer agents. PROTAC is therefore expected to offer a new approach to the treatment of cancer, beyond the limitations of existing drugs.
◇ Ubix develops the “Immuno-Anticancer Agent Targeting Epigenetic Checkpoint”
Ubix Therapeutics has secured the “Degraducer” technology that is differentiated by direct coupling with CRBN (Cereblon), one of the E3 ligases, from other technologies, and has patented the technology globally. In the course of the development of Degraducer technology, the excellent performance of proteolysis and the efficacy of cytotoxicity against diverse targets, including verified items such as IKZF1/3 and BRD4 etc., were identified.
Ubix Therapeutics is now developing a new immuno-anticancer drug that uses Degraducer technology to target the epigenetics of the chromatin and immune-checkpoint proteins.
Epigenetics is a genetic control system that regulates gene expression. Recently, an interesting report suggests that epigenetics is involved in the immune-checkpoint. The epigenetic inhibitors, such as BET, DNMT, HDAC, and EZH2, control the expression of PD-L1. This signifies that epigenetic inhibitors can produce synergetic effects by being employed as combined therapy with immune-checkpoint inhibitors and T-Cell immuno-therapies.
◇ ‘Degraducer’ technology revealed the excellent performance of proteolysis
The first target of Ubix Therapeutics is the Bromodomain-containing protein 4 (BRD4). Bromodomain (BRD) is an epigenetic gene involved in the control of gene transcription and enzyme of structural change of the chromatin. BRD4 causes cancer by expressing tumor -related genes, such as EZH2 and c-Myc etc., through the formation of p-TEFb complex, together with CDK9 and Cyclin T. JQ-1, the BIT inhibitor, OTX015 (Merck), and I-BET762 (GSK) etc. are in clinical trials targeting BRD4 for cases of hematologic malignancy and solid cancers, etc. However, PROTAC technology can be taken as a new alternative for proteolysis, since it is difficult for existing drugs to attain selective inhibition of BRD4 specifically, with issues of drug tolerance remaining unresolved.
In fact, Arvinas demonstrated that BRD4 can be degraded by PROTAC technology. The “ARV-825”, composed of “BRD4 inhibitor (JQ1)-PEG Linker-CRBN Binder”, decreased the level of BRD4 rapidly within 6 hours, and its effect was sustained over 24 hours. The “ARV-771”, the VHL-bound PROTAC linked to JQ1, manifested the delay of progress of leukemia of xenogenic graft model of mouse.
Ubix Therapeutics has also identified the performance of the degradation of BRD4 through Degraducer technology. The JQ1, the BRD4 inhibitor that was used in ARV-825 of Arvinas, was used as it was, and the comparative experiment was conducted by combining E3 ligase binder with the linker of Ubix Therapeutics.
President Seo emphasized, “..we have witnessed the effective degradation of BRD4 through our own technology”, “in particular, the cytotoxicity was identified through the degradation of BRD4, from which its anticancer effect was also identified, which is superior to that of Arvinas.” Ubix Therapeutics now challenges the treatment of solid cancers, such as breast cancer, through the degradation of BRD4.
Ubix Therapeutics is also developing the next-generation immune-checkpoint inhibitor. Different from existing receptor drugs in the PD-1 family, such as Keytruda and Opdivo, the new drug employs a strategy of attacking the target protein involved closely with immune-checkpoint inhibitor in the intra-immunocyte signal transmission system. In particular, the company is developing the next-generation immune-checkpoint inhibitor that enables the combined administration with drugs of the PD-1 family, by activating immunocytes, through aiming at specified targets in Treg and CTL.
◇ Competitiveness of Ubix Therapeutics: “Pipeline Scalability & Group of Excellent Researchers”
So, what is the key feature of PROTAC technology? President Seo explained, “... the optimization in inter-component configuration comprising E3 ligase binder, target ligand, and the linker connecting these two components, is most important in the development process of PROTAC drug. Even the performance for the degradation of optimized PROTAC varies depending on the type of target proteins; therefore, diverse kinds of E3 ligase binders are being developed. Ubix Therapeutics will expand its diversity in terms of the PROTAC platform.”
The competitiveness of Ubix Therapeutics is based on its Pipeline expandability realized through secured platform technologies. President Seo stated, “... Securing platform technologies enables our company to compete with other competitors in the global market, and will enable our company to flexibly cope with issues associated with sustainability, regardless of the success or failure of any one pipeline. Diverse strategies for respective commercialization by exploiting the platform technologies can also be enabled...”
Ubix Therapeutics will promote the export of technologies to domestic and overseas pharmaceutical companies, based on the results that will be obtained from the non-clinical and initial clinical trials of the pipeline in the process of development. The company is also considering entering into global markets with its key pipeline through multi-national clinical trials to be held in the U.S.A., and in countries of the EU. Cooperation with partner companies having spontaneous targets through licensing the PROTAC platform technologies is also anticipated.
The company has also secured an excellent group of researchers. The faculty of the advisory board currently consists of professional researchers who are specialized in the fields of the development of new low molecular drugs, evaluation of functions and structural analysis of protein, development of an algorithm deriving CADD and small molecule HIT, and in the mechanism of Ubiquitin-Proteasome. The internal competence of the company comprised of prominent chemists and biologists will be exploited for the fast completion of effective research and development.
President Seo suggested his aspiration was as follows: “... from a global perspective, the PROTAC technology is now at the stage of its quickening period, wherein the stage of development of the pipeline of the most advanced treatment is now at the stage of completion of non-clinical trials. In about 2105, the PROTAC technology reached the stage where it could be employed for the development of new drugs. Sharing similar starting points with others would be a fortunate aspect for us. The advantages and expandability of the platform technology of UBix Therapeutics will be exploited for the development of therapeutics for intractable diseases, and will promote us into becoming a global bio-therapeutics company.”