BOC Sciences is a leading CRO focused on the development of targeted protein degradation molecules and we have established a well-established PROTACs development platform. We provide customized services for one-stop development of PROTACs targeting KDM5B based on customer-specified KDM5B targets.
Overview of KDM5B
KDM5B, also known as JARID1B, is a histone demethylase that has been identified as a potential target for cancer therapy. KDM5B specifically demethylates histone H3 at lysine 4 (H3K4), a modification that is associated with transcriptional activation of genes. KDM5B is frequently overexpressed in a variety of cancers, including breast, lung, and prostate cancer, which has been shown to play a role in cancer cell proliferation, survival, and metastasis. Several small molecule inhibitors of KDM5B, such as JIB-04 and CPI-455, have been developed and shown to have anti-cancer activity in preclinical studies.
Introduction of KDM5B-PROTACs
PROTACs, or Proteolysis-Targeting Chimeras, have emerged as a promising strategy for targeted protein degradation. PROTAC recruits an E3 ubiquitin ligase to a target protein, resulting in ubiquitination and subsequent degradation of the target protein by the proteasome. Recently, several KDM5B-targeting PROTACs have been developed and shown to effectively degrade KDM5B in cancer cells. For example, studies reported a KDM5B-targeting PROTAC named LJM-3064, which was able to degrade KDM5B in breast cancer cells and inhibit their proliferation; and a KDM5B-PROTAC called MS452, which was able to degrade KDM5B in lung cancer cells and inhibit their growth both in vitro and in vivo. KDM5B-targeting PROTACs have the potential to be a promising new approach for cancer therapy by inducing targeted protein degradation of KDM5B. Further research is needed to optimize the potency and specificity of KDM5B-targeting PROTACs and to evaluate their safety and efficacy in preclinical and clinical studies.
Advances in KDM5B-PROTACs
Studies have reported the use of bifunctional ligands to enhance the specificity and potency of KDM5B-PROTACs. Bifunctional ligands contain two different ligands that bind to different sites on the target protein and promote more effective target degradation. For example, JBJ-04-125-02 is a KDM5B-PROTAC that contains a bifunctional ligand that binds to both the KDM5B catalytic site and an adjacent protein-protein interaction site. In addition, several studies have recently focused on the pharmacological properties of KDM5B-PROTACs, such as their oral bioavailability and metabolic stability. Improving the pharmacokinetic properties of KDM5B-PROTACs by optimizing their chemical structure may help translate them into the clinic.
Our Services for KDM5B-PROTACs
The E3 ligase must have a high affinity for the target protein and be able to ubiquitinate it efficiently. The potential E3 ligases for KDM5B includes von Hippel-Lindau (VHL), CUL4A-DDB1-CRBN (CRL4CRBN), and MDM2. It is notably that VHL is the most commonly used E3 ligase for KDM5B-PROTAC development.
The linker should be long enough to allow the ligand to bind to the target protein, while also allowing the E3 ligase-binding moiety to interact with the E3 ligase. The linker should also be flexible to allow for the necessary conformational changes that occur during the degradation process. Optimizing linker length and flexibility may improve the activity of KDM5B-PROTAC.
The development of KDM5B-PROTACs requires careful optimization of their overall structure to ensure target selectivity, potency, and pharmacokinetic properties. One approach to optimizing KDM5B-PROTACs is to optimize the linker region between the E3 ligase ligand and KDM5B warhead. Another approach to optimizing KDM5B-PROTACs is to modify the ligands that are used to recruit the E3 ubiquitin ligase and KDM5B, respectively. And the activity of KDM5B-PROTACs will be assessed by ternary complex formation, in vitro cellular activity, or target protein degradation levels.
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
