protac reviews,

PROTAC consists of a flexible linker conjugating the protein of interest (POI) ligand and an E3 ligase ligand. Its action mechanism makes use of the mechanism of protein degradation induced by the ubiquitin-protease system in vivo. One end of the drug molecule specifically binds to the target protein, while the other end recruits ubiquitin E3 ligase to form the ternary complex of target protein-PROTAC-E3 ligase. After putting the ubiquitin tag on the target protein, it induces a ubiquitin-mediated protease system to degrade the target protein.

  1. BCR-ABL

BCR-ABL has become a potential target of anticancer drugs in chronic myelocytic leukemia (CML). Imatinib was the first Tyrosine Kinase Inhibitors (TKI) targeting BCR-ABL. Subsequently, a variety of ABL kinase inhibitors, including bonatinib, dasatinib, nilotinib and bosutinib, have been approved for clinical use. Although the use of TKI improves the treatment outcome of CML, long-term treatment and drug resistance remain major challenges.

Studies have found that the degradation of BCR-ABL may be beneficial to the treatment of CML. A new anticancer agent SNIPER (ABL)-062 has been reported, which has a strong binding affinity to cIAP1/2, ABL1, and XIAP, resulting in complete degradation of BCR-ABL and inhibition of BCR-ABL-mediated signal pathway, resulting in the degradation of carcinogenic proteins.

Zhao speculated that optimizing the structure of the junction could promote the interaction between BCR-ABL and E3 ligase. Based on this assumption, they developed a powerful BCR-ABL degrader SIAIS178. SIAIS178 showed obvious selectivity in vitro and significantly inhibited the growth of BCR-ABL+ leukemia cells. In vivo, it had a significant inhibitory effect on the K562 xenograft tumor.

Yang et al. reported P19P targeting dasatinib, bonatinib, and asciminib binding sites in BCR-ABL protein. In addition, Crews found that GMB-475 could induce rapid proteasome degradation and showed higher sensitivity.

  1. PI3K-Akt

Phosphatidylinositol 3-Kinase (PI3K) is an intracellular lipid kinase, which plays a role in cell survival, proliferation, growth, differentiation and migration, and is a potential anticancer target. PI3K can be divided into three categories, among which class I is widely studied. Most cancer cells show overactivated mutations of type I PI3K, which drive tumor cell proliferation and survival.

Li developed a novel PI3K-PROTAC by combining pomalidomide with piperazine derivatives using different connectors. These compounds can significantly inhibit PI3Ka and the IC50 value is at nanomole level. Among them, compound B is the most effective, and its IC50 to PI3Ka is 18 nM. In addition, Tovell reported the use of SGK3-PROTAC1 for selective degradation of SGK3. SGK3-PROTAC1 at sub-micromolar concentration can induce proteasome-mediated degradation in different cancer cell lines.

  1. BTK

BTK promotes the growth, maturation, migration and apoptosis of B cells. Cancer, autoimmunity, or inflammation may be caused by disorders of the BTK pathway. So far, considerable progress has been made in the research of BTKs, and BTK inhibitors such as ibrutinib, acaratinib and zanubrutinib have been approved by FDA. However, BTK inhibitors still have some limitations, such as drug resistance and off-target effects.

Recently, Buhimschi reported MT802, which connects BTK-specific ligands and CRBN ligands through PEG connectors. Compared with irutinib, this compound can degrade BTK more effectively. Jaime-Figueroa further modified the ligand structure of CRBN and synthesized SJF620, which showed better pharmacokinetic characteristics than MT802 in mice. Based on the previous work, some researchers further optimized the compounds and synthesized PROTAC 7, TL12-186, SPB5208, and P13l, respectively.

Sun also developed L18I, which can induce BTK degradation of nairutini in HBL-1 cells at 30 nM. Excitingly, L18I played a significant anti-tumor effect in drug-resistant tumor fine culture mice. So far, most of the reported PROTAC works through covalent or non-covalent binding. Irreversible covalent inhibitors have strong target affinity and high target occupancy, and have been successful in the clinical environment.

However, irreversible binding may reduce the anti-tumor efficacy by reducing the catalytic activity of PROTAC. Dittus developed PROTAC 2 and PROTAC 3 by selecting covalent inhibitor irutinib and reversible binding analogues and investigated their BTK degradation ability. PROTAC 2 did not degrade the covalently bound target protein, while PROTAC 3 degraded its target protein. This finding emphasizes the importance of catalysis for successful PROTAC-mediated degradation. In addition, reversible covalent inhibitors are selective and can increase anti-tumor efficacy. In order to improve the efficiency of PROTAC, Gabizon and Guosynthesized efficient and reversible covalent RC-3 and RC-1 respectively.

  1. RTK

RTK plays a key role in controlling the basic cellular processes and regulating the signaling pathways of intercellular communication. As a kind of RTK, EGFR is closely related to the regulation of apoptosis, proliferation, metabolism, and survival. The overexpression and activation mutation of EGFR are related to several types of cancer. Uncontrolled activation of EGFR leads to abnormal cell growth, which may lead to endocytosis of EGFR signal and intracellular terminal transport. Recently, some small-molecule and antibody targeted therapeutic drugs targeting EGFR have been developed for cancer treatment. So far, the FDA has provided more than a dozen EGFR inhibitors to patients with non-small cell lung cancer, but EGFR mutations may affect drug efficacy.

PROTACs can degrade several kinds of RTK, including cMet, HER2, EGFR, mutants of EGFR, and c-Met. Konecny synthesized a new PROTAC by conjugating EGFR binding element Lapatinib with E3 ligase binding ligand. At low nanomole concentration, the compound showed cell membrane permeability and EGFR degradation.

  1. FAK

FAK, a cytoplasmic tyrosine kinase, was first reported in 1992. FAK promotes tumor growth, invasion, and metastasis in a kinase-dependent manner. Some studies have shown that the increase of expression and activity of FAK in primary and metastatic cancer tissues is not conducive to the survival of patients, and inhibition of FAK can potentially prevent tumor progression.

At present, the clinical effects of small molecular FAK inhibitors have been investigated. Unfortunately, FAK has kinase-dependent and kinase-independent functions, which means that FAK inhibitors can antagonize its kinase-dependent function, but not kinase-independent function. However, PROTAC targeting FAK can inhibit both kinase-dependent and kinase-independent functions.

  1. CDK

It has been reported that in the CDK family, CDK1-4, CDK11, and CDK6 regulate the cell cycle, while CDK7-9 mainly regulates transcription. Studies have found that in tumor models, small molecular CDK inhibition can inhibit cell growth and promote cell cycle arrest, thus promoting cell apoptosis, which is a promising cancer treatment strategy.

In 2015, the first selective CDK4/6 inhibitor palbociclib was approved by the FDA for the treatment of metastatic BC. In addition, terminally differentiated cells showed increased expression of CDK9. Some studies have found that selective CDK9 inhibitors have the potential to treat a variety of diseases, including cancer. A great deal of evidence shows that CDK9 is a potential target for tumor therapy, but adverse reactions and toxicity limit the wide clinical application of CDK9 inhibitors. Therefore, it is necessary to formulate feasible treatment strategies.