(Health Korea News / Soon-ho Lee) Dongwha Pharmaceutical is showing moves to add a pipeline of new drugs to treat immune diseases. The company has begun the patent registration process based on joint research with Simplex, an AI-based new drug development venture company. It appears that the optimal candidate material has been found through experiments, so attention is being paid to whether the development of a treatment will begin in earnest.
The Korean Intellectual Property Office recently disclosed the specification of the patent application for ‘Novel carboxamide derivative compound and pharmaceutical composition containing the same’ that Dongwha Pharmaceutical and Simplex applied together in June last year. This application relates to an IRAK-4 or IRAK-1 inhibitor, and is the first material patent application for an immune disease treatment that both companies plan to develop.
IRAK is a serine/threonine kinase responsible for downstream signaling of TLR in the ‘interleukin 1-tolike receptor (IL-1R/TLR)’ signaling pathway involved in innate immunity and inflammation. IRAK-1 There are four subtypes, including , IRAK-2, IRAK-M, and IRAK-4. Among these, research is mainly on IRAK-4 and IRAK-1, which have a kinase function.
IRAK, responsible for IL-1R/TLR downstream signaling
IRAK-4 and IRAK-1 research most active
The IL-1R/TLR signaling pathway is involved in the development of various inflammatory and autoimmune diseases such as sepsis, asthma, arteriosclerosis, Alzheimer’s, rheumatoid arthritis, atopy, hidradenitis suppurativa, psoriasis, rheumatoid arthritis, ulcerative colitis, and lupus. It has been reported.
In particular, when pathogen-related molecular patterns commonly expressed in various pathogens and damage-related molecular patterns released from stressed or dying cells bind to IL-1R/TLR, downstream signaling mechanisms are activated, resulting in an inflammatory response. If this inflammatory reaction continues, it can develop into cancer.
To prevent or treat IL-1R/TLR-related diseases, it is necessary to block TLR itself, which plays an important role in the IL-1R/TLR signaling pathway, or inhibit IRAK, which is responsible for downstream signaling of TLR. In particular, the most research is being done on IRAK-4, which plays an important role in forming myddosomes in the IL-1R/TLR signaling pathway, and recently, research on IRAK-1 has been actively conducted.
Against this background, Dongwha Pharmaceutical and Simplex developed a compound with a new structure that strongly inhibits IRAK-4 or IRAK-1, and confirmed its effectiveness in inhibiting IRAK-4 and IRAK-1 proteins and inflammatory cytokine secretion.
Dongwha Pharmaceutical and Simplex conduct experiments with 178 substances
Confirmed excellent IRAK-4·1 and TNF-α inhibitory effect
Researchers from both companies discovered a total of 178 substances, divided them into two groups (53 and 125 substances, respectively), and then conducted experiments to inhibit IRAK-4 and IRAK-1 protein activity and to inhibit secretion of cell-based inflammatory cytokines. did it
First, in the experimental group consisting of 53 substances, the substance with the best IRAK-4 protein inhibition effect, IRAK-1 protein inhibition effect, and inflammatory cytokine secretion inhibition effect was derived. The name of the compound is ‘N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(1H-pyrazol-5-yl )Benzamide’.
The inhibitory effect of this substance on IRAK-4 protein was 97.9% at a concentration of 1 micromolar (uM) and 89.3% at a concentration of 0.1uM. The IRAK-1 protein inhibition effect was 82.40% at 1uM concentration and 67.20% at 0.1uM concentration, and the IRAK-4 protein and IRAK-1 protein inhibitory effects were the highest among the compared experimental substances.
The 50% inhibitory concentration (IC50 value) of TNF-α, an inflammatory cytokine, was 11.9 nanomol (nM), the lowest among the compared test substances. IC50 refers to the concentration of drug required to reduce the activity of a biological reaction by half.
In the experimental group consisting of 125 substances, more diverse substances showed high inhibitory efficacy on IRAK-4, IRAK-1, and TNF-α, and among them, ‘N-(2-(3-hydroxy-3-methylbutyl)-6-( ‘4-Hydroxyphenyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide’ showed the most notable effect.
This compound had an IRAK-4 protein inhibition effect of 98.1% at a concentration of 1uM and 85.6% at 100nM. The IRAK-1 protein inhibition effect was close to 100% at 10uM. Additionally, the 50% inhibitory concentration (IC50 value) of TNF-α was 0.7nM, which was the lowest among the comparative test substances.
Joint ownership of research results
The exclusive license is Dongwha Pharm.
Previously, Dongwha Pharmaceutical signed a joint research and development agreement with Simplex in March 2022 to develop a treatment for immune diseases.
Under this contract, Simplex will use ‘CEEK-CURE’, an ‘Explainable AI’ platform, to discover optimal new drug candidates for immune disease treatment, and Dongwha Pharmaceutical will develop and synthesize active substances and candidate substances. We decided to proceed with verification and secure the pipeline.
Joint research results produced through cooperation are jointly owned by both companies, but Dongwha Pharmaceutical has an exclusive license.
Simplex is a venture company founded by CEO Cho Seong-jin, who majored in medicinal chemistry and has experience developing new drug development platforms at global pharmaceutical company BMS and bio company Amgen. We are collaborating with a number of pharmaceutical and bio companies such as Dong-A ST and SK Chemicals.
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