Ligand Screening for cIAP1-based PROTAC

Creative Biolabs is a leading expert in small molecule drug development. The company has carried out a lot of research and exploration especially on PROTAC technology. We can provide professional and efficient related services to help accelerate the development of PROTAC-based therapeutics.

Introduction to cIAP1

cIAP1 is also called BIRC2, and its full name is a cellular inhibitor of apoptosis protein-1. cIAP1 belongs to the IAP protein family. It is a multifunctional protein that exists in the cytoplasm and the nucleus of tumor cells. cIAP1 is located in different positions at different stages of the cell life cycle. In healthy cells, cIAP1 is often located in the nucleus, and when the cell is apoptotic, the nucleus will export the protein and cause the cIAP1 concentration in the cytoplasm to rise. However, when cells begin to become cancerous, cIAP1 is still located in the nucleus of cancerous cells because it needs to continuously proliferate and which thus inhibits apoptosis.

cIAP1 is an inhibitor of apoptotic proteins. It works by directly ubiquitinating RIP1 and inducing ubiquitination of constitutive RIP1 in cancer cells. cIAP1 plays an important role in the growth and development of many cancers. Overexpression of cIAP1 will lead to the proliferation of pancreatic, liver, lung and oesophageal cancer. cIAP1 also has a significant influence on maintaining endothelial cells and vascular homeostasis. Variations or abnormalities of the proteins may cause problems such as bleeding and vascular regression.

cIAP1 expression in gallbladder cancer (GBC) tissues and non-tumor tissues. Fig.1 cIAP1 expression in gallbladder cancer (GBC) tissues and non-tumor tissues. (Wei, 2019)

Ligand Design for cIAP1-based PROTAC

The gene encoding cIAP1 is located in chromosome 11 and encodes a total of 618 amino acids. cIAP1 has a unique protein chain, and contains at least one BIR (baculoviral IAP repeat) domain, which helps it to bind to caspases and other proteins. The tertiary structure of cIAP1 consists almost entirely of the alpha helixes.

As an E3 ubiquitin ligase, cIAP1 can cause ubiquitination of RIP1 and thus promotes the proliferation of various tumor cells. Therefore, cIAP1-based PROTAC has also become a direction for the design and development of effective PROTAC, and cIAP1 currently has corresponding small molecule ligands. Among them, methylbestatin (MeBS) can bind to baculoviral IAP repeat domain of cIAP1. Thereby, a PROTAC linking MeBS with ATRA (all-trans retinoic acid, a CRABP-I and II inhibitor) was designed and prepared. The experimental results show that the cIAP1-based PROTAC can induce the ubiquitination and degradation of CRABP-I / II protein in cells. Other cIAP1-based PROTACs have also been designed to target the degradation of proteins such as RAR, ER, AR, and TACC3.

Structure of three cIAP1. Fig.2 Structure of three cIAP1.

It is worth noting that some disadvantages of MeBS being cIAP1 ligand are its low selectivity and lack of activity, so the activity of PROTAC designed with MeBS is also difficult to be satisfying. Based on years of drug screening and development experience, and combined with the company's advantages in antibody development, Creative Biolabs provides customers with professional and efficient services in screening more active and more specific cIAP1 ligands from forms of small molecules, peptides to even antibodies. As an important strategy in the field of drug development, new and improved applications of old drugs are also a direction for us to develop PROTAC. Structural modification and optimization of existing cIAP1 ligands is also the content of our research and services.

Advantages

  • World-class research and development team in PROTAC technology
  • Years of PROTAC-based drug development experience
  • Solid foundation in small molecule drugs, peptides, and antibodies development
  • One-stop service system from PROTAC design to production to evaluation

Creative Biolabs has long-term devoted to the development of PROTAC. Our scientists are confident in offering the best and most suitable ligand design for our customers all over the world. If you are considering developing novel PROTACs against the target of interest, please do not hesitate to contact us for more details.

Reference

  1. Wei, Su.; et al. cIAP1 promotes proliferation and migration and prevents apoptosis in gallbladder cancer in vitro. Biosci Rep. 2019 Apr 30; 39(4): BSR20182266.
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