Ligand Design for BCR-Abl-targeting PROTAC^®

Abl kinases are a class of prototypic cytoplasmic tyrosine kinases that participate in a number of chromosomal aberrations in various cancers. The activity of Abl kinases leads to the expression of Abl fusion proteins that are constitutively activated and become drivers of tumorigenesis, for example, BCR-Abl. As a leading CRO company, Creative Biolabs provides comprehensive ligand design services for BCR-Abl-targeting PROTAC^®, which offers more sensitivity to drug-resistant agents and the potential to affect nonenzymatic properties.

• Introduction to BCR-Abl

Crystallographic analysis of BCR-Abl emphasizes a two-lobe catalytic region, respectively comprising N- and C-lobes towards N- and C-terminus of the protein sequence. Among them, α-helices compose the latter, while β-sheets prevail in the former. A key phosphate-binding (also known as Walker loop or P-loop) links two β-sheets of N-lobe. Since its high flexibility, a Walker loop residue can interpose between β- and γ-phosphates of bound ATP, so that facilitating phosphoric anhydride bond break after nucleophilic attack from the catalytic loop (Asp363). The hinge region, which connects the two lobes, also engages in ATP binding via two hydrogen bonds. Within the ATP-binding pocket, a gatekeeper residue (Thr315) as well interacts with ATP. This site is located at the peak of one of the multiple hydrophobic spikes linking N- and C-lobes in an active conformation. Additionally, it plays a pivotal role in conferring selectivity to some of Bcr-Abl inhibitors.

Fig.1 Structural 3D model of the Bcr-Abl catalytic domain. (Rossari, 2018)

Chronic myeloid leukemia (CML) is known as a myeloproliferative disorder characterized by the presence of certain oncogenic proteins, such as BCR-Abl. This protein is produced by a balanced translocation between the c-Abelson (Abl) on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22. Development of tyrosine kinase inhibitors (TKIs) specific to Abl (e.g. imatinib) has dramatically improved prognosis for CML patients by blocking BCR-Abl activity without destroying the normal cells. Currently, PROTAC^® has been used to link inhibitors to BCR-Abl for treating CML.

• Ligand Design Services for BCR-Abl at Creative Biolabs

The manipulation of protein stability with small molecules has a large market as a powerful tool for assisting the development of clinical therapeutics, including treatments for cancers. At Creative Biolabs, we have launched multiple PROTAC^® platforms to cross the hurdles of current drug discovery and development in biology, and take efforts to get a deeper insight into the safety and efficacy of BCR-Abl-targeting PROTAC^®s in clinical routine.

Fig.2 Approach to PROTAC^® development. (Lai, 2016)

As one of the fusion partners in the BCR-Abl, Abl includes an allosteric myristylation binding site acting in the autoinhibited state of proteins and many compounds are developed to target that region. Recently, our experts have successfully established a series of PROTAC^®s targeting BCR-Abl kinases and there’re diverse modalities of their ligands can be used for development, including small molecules, peptides, as well as antibodies. In the development process, we optimize synthetic strategies for PROTAC^® design that incorporates variations in E3 ligases and warheads, allowing to rapidly assess the degradation profiles.

• Key Benefits
  • One-stop, customized services for specific PROTAC^® development
  • Cost-effective and time-saving projects to advance clients’ research
  • State-of-the-art techniques equipped with dedicated facilities

PROTAC^® technology has extensively investigated throughout the world and has outperformed in cancers, immune disorders, viral infections, and many others. With abundant experience in drug discovery, Creative Biolabs provides ligand design services for PROTAC^® development. For more details, please don’t hesitate to contact us.

References

1. Rossari, F.; et al. Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy. J HEMATOL ONCOL. 2018, 11(1): 1-14.
2. Lai, A.C.; et al. Modular PROTAC^® design for the degradation of oncogenic BCR-ABL. Angew Chem Int Ed. 2016, 55(2): 807 -810.