PROTACs Targeting Protein Kinases

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As a CRO that has been deeply involved in the field of PROTAC for over a decade, BOC Sciences provides various PROTAC targeting services, such as PROTAC design and synthesis, target validation, and drug molecule activity assay. PROTAC is a targeted protein degradation technology that is considered promising for targeting 'undruggable' disease-related proteins.

As an essential class of therapeutic targets for anticancer drug development, protein kinases are included in our comprehensive PROTAC targeting services. With extensive expertise in PROTAC targets, we provide drug development services for PROTAC molecules to target protein kinases.

Introduction

Various diseases were demonstrated to cause by the mutation or accumulation of specific proteins, and specific degradation of these pathogenic proteins can intervene in or cure diseases, which reserved great scientific and clinical value. Among them, protein kinases, as critical therapeutic targets for anticancer drug development, are closely related to cell proliferation, migration, and survival.

Small molecule inhibitors can interfere with the biological activity of protein targets based on specific active sites. However, for most protein kinases, suitable targeting sites are still lacking. Unlike small molecule inhibitors, the ligand targeting protein kinase in PROTAC does not necessarily bind to the active site and overcome the disadvantages of small molecule inhibitors. Therefore, PROTACs possessed great advantages in overcoming target mutations.

Services of PROTACs Targeting Protein Kinases

We are capable of providing services for the development of PROTAC molecules targeting protein kinases. In addition, we offer PROTAC molecular optimization services, including optimization of ligands and linkers to facilitate interactions between protein kinase and E3 ligase. To date, PROTAC technology has been applied to various protein kinase targets, including BCR-ABL, PI3K, BTK, RTK, FAK, CDK, and MEK1/2.

  • Targeting PI3K

Phosphatidylinositol 3-kinase (PI3K) is an intracellular lipid kinase that plays an essential role in cell survival, proliferation, growth, differentiation, and migration. The development of novel PI3K-PROTAC has been reported by combining pomalidomide and piperazine derivatives using different linkers, and these compounds can significantly inhibit PI3Ka at nanomolar levels according to the IC50 values.

Bruton's tyrosine kinase (BTK) promotes B-cell growth, maturation, migration, and apoptosis. Furthermore, cancer, autoimmune or inflammatory diseases may be caused by BTK pathway dysregulation. The development of BTK inhibitors has remained limited such to drug resistance and off-target effects. PROTAC, consisting of BTK-specific ligand and CRBN ligand linked via the PEG, was reported to be effective in degrading BTK.

  • Targeting RTK

Tyrosine kinases (RTK) play key roles in signaling pathways that control essential cellular processes and regulate intercellular communication. PROTACs degrade several RTKs, including cMet, HER2, EGFR, as well as multiple mutants of EGFR and c-Met.

  • Targeting BCR-ABL

BCR-ABL has emerged as a potential anticancer drug target in chronic myelocytic leukemia (CML). The degradation of BCR-ABL was potentially beneficial for CML treatment, and PROTAC can be a potent anticancer drug for the degradation of this oncogenic protein.

  • Targeting FAK

Focal adhesion kinase (FAK) promotes tumor growth, invasion, and metastasis. It has been shown that inhibition of FAK can potentially halt tumor progression. Currently, highly selective PROTAC targeting PTK2 degradation has been developed.

  • Targeting CDK

Among the cyclin-dependent kinase (CDK) family, CDK1-4, CDK11, and CDK6 regulate the cell cycle, while CDK7-9 mainly regulates transcription. A variety of PROTACs has been reported to be developed to degrade different CDK members.

  • Targeting MEK1/2

RAS-RAF-MEK-ERK is involved in various cellular processes, such as proliferation, differentiation, apoptosis, migration, and metabolism. In addition, MEK1 and MEK2 play an essential role in regulating ERK activity. PROTAC has been reported to be a durable and effective candidate in degrading MEK1 and MEK2.

Our Advantages

  • Multiple PROTAC technologies to meet different customer needs
  • Quality one-stop service
  • Experienced experience in developing small molecule drugs targeting protein kinases
  • Highly reliable and reproducible result
  • Short turn-around time and competitive price
  • Data analysis, detailed report with results and discussion

Project Workflow

Project Workflow

References:

  1. Yu, F., Cai, M., Shao, L., and Zhang, J., Targeting Protein Kinases Degradation by PROTACs, Front. Chem., 2021, 9:679120.
  2. Qi, S., et al. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy, Front. Pharmacol., 2021.

* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.

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