Preclinical results of protein degradation therapy actively reduce target protein levels by 75%

The "Umolife/E3 Uenzyme" system in the human body is a natural system that maintains a balance of protein production and degradation and is responsible for initiating the destruction of abnormal regulatory functions, folding or synthesis of incorrect proteinsOften small molecular inhibitors want to function by blocking catalytic sites or combining them with "pockets" that can affect protein functionIn contrast, targeted protein degradation agents can theoretically bind to any corner of the protein to drive protein degradationtargeted protein degradation agent is designed to be combined with the target protein at one end and e3 ubiquinone in one end through a small molecule with two active endsThis allows the target protein to be ubiquitized and then transported to the cell's "waste treatment station" - proteasome, for degradationa diagram of the workings of the protein degradation agent sampon sampon (Photo: Kymera official website)target protein degradation agenthas have several potential advantages:the greatest theoretical advantage is that they allow previously unviable targets to be targeted by drugs, which may solve 80% of the non-pharmacological targets in various cancer cells (undrugable targets)Degradation agent compounds are usually soluble, can penetrate into cells, can be taken orally, and can resist the degradation of metabolic processes, and even some can cross the blood-brain barrier to treat diseases of the central nervous systemprotein-targeted degradation agent can be released after the protein has been degraded and continues to target other proteins, thus rapidly reducing the target protein levelThere is the potential to separate pharmacodynamics from pharmacokinetics, which means that short-term degradation agent effects may have long-term effects on signaling pathwaysMYD88 mutation sympain is common in several subtypes of B-cell lymphoma, such as 30-40% of active B-cell diffuse large B-cell lymphoma (ABC-DLBCL) casesMYD88 mutations can lead to the activation of the IRAK4 kinaseAs a serine/sine kinase, IRAK4 plays a key role in the innate immune system and is associated with a variety of cancersTHE NON-KINASE EFFECT OF IRAK4 IS USED AS A SKELETON PROTEIN TO HELP BUILD PROTEIN COMPLEXES IN THE INNATE IMMUNE SYSTEMTherefore, the protein degradation agent targeted at IRAK4 may achieve completely unique and better efficacy than the IRAK4 inhibitorResults presented at the conference showed that in myD88 mutants, or MYD88 wild ABC-DLBCL cell lines, the IRAK4 degradation agent KYM-001 was able to effectively degrade IRAK4 by relying on E3 connective enzymes In the ABC-DLBCL xenotransplant edsotic tumor model of ABC-DLBCL, which carried the MYD88/CD79 mutation, KYM-001 allowed the tumor to subside and reduce the IRAK4 level by up to 75% In addition, the combination of KYM-001 and ibrutinib can promote apoptosis of tumor cells 's Kemera's product development pipeline (Photo: Kymera's official website) "These data show that IRAK4's oral protein degradation agents can be used as both a single-drug therapy and complementary to other targeted therapies to treat B-cell lymphomas with mutations in the MYD88 gene," said Jared Gollob, Chief Medical Officer of Kymera These data are a great encouragement to Kymera and strongly support our in-depth clinical study of KYM-001 References: Retrieved June 20, 2019, from https:// 2 s lymphoma Retrieved June 20, 2019, from https:// protein degradation therapy is about to enter clinical and its potential and limitations are something you must know Retrieved June 20, 2019, from https://mp.weixin.qq.com/s/s6ty0z0tWYc8XnqGofIKTQ