Protacs may be a great opportunity for academia and Industry

Proteolysis targeting chimeras (protacs) has become a promising technology to regulate protein of interest (POI) by degradation< br / > 1Principle < br / > protacs technology like dumbbells (picture source: David Parkins) < br / > as shown in the above figure, protacs technology looks like dumbbellsThis bifunctional molecule connects the ligands of interest proteins and recruitment ligands of E3 ubiquitin ligase through an ideal linkerThat is to say, one end of protacs technology binds to interest protein (i.etarget protein) and the other end binds to E3 ubiquitin ligaseE3 ubiquitin ligase marks a small protein called ubiquitin as defective or damaged by attaching it to a protein of interestAfter that, the cell's protein Shredder (i.e., proteasome) processes the tagged proteins of interestIn other words, when protocs promote the formation of ternary complex of interest protein and E3 ubiquitin ligase, degradation will occur, thus regulating the level of interest proteinThe mode of action of < br / > protacs | a part of ubiquitin proteasome system (UPS) in eukaryotic cells, 26S protease can recognize and degrade the ubiquitin protein of interest (source: signal transmission and targeted therapy) < br / > the discovery of protacs dates back to 2001At that time, DrRaymond Deshayes of Caltech and Professor Craig crews of Yale University described in a PNAs paper [1] that peptide based protac-1 was used to induce the degradation of target protein type 2 methionine aminopeptidase (metap-2)However, a generation of protocs based on large and bulky peptides as a linker has low activity in human cells, and Professor crews and his colleagues have been improving the technology sinceBy 2008, they had abandoned peptide based protacs technology and designed a small molecule based protacs based on E3 ubiquitin ligase MDM2, which can be used to degrade androgen receptor (AR) [2]Since then, scientists have developed a large number of protacs that can degrade different proteins of interestThe range of targets and types of diseases that protacs can reach have expanded / increased at an amazing rate< br / > 2 Target < br / > recently, Professor Rao Yu's team of Tsinghua University published a review article entitled "protocs: great opportunities for academia and industry" in the Journal of signal transportation and targeted therapy under nature [3], This paper summarizes the cancer related targets, virus infection related targets targeted by protacs and the application of protacs in the treatment of immune diseases and neurodegenerative diseases < br / > distribution of protacs | a the effectiveness of protacs in different diseases; B the effectiveness of protacs in different biological processes (source: signal transmission and targeted therapy) < br / > ① cancer related target < br / > target 1: AHR (aryl hydrocarbon receptor) < br / > Introduction: AHR mediates many toxic and carcinogenic effects of environmental carcinogens < br / > representative protocs: api-protoc-ii < br / > target 2: ALK (anaplastic lymphama kinase) < br / > Introduction: the carcinogenic activation of ALK is highly related to the occurrence and development of various cancers, It includes diffuse large B cell lymphoma, anaplastic large cell non Hodgkin's lymphoma, esophageal squamous cell carcinoma, inflammatory myofibroblastoma, non-small cell lung cancer, renal cell carcinoma, neuroblastoma, thyroid cancer, ovarian cancer, colon cancer and breast cancer < br / > representative protocs: tl13-12, tl13-112, ms4077, ms4078, td-004 < br / > target 3: AR (Android receiver) < br / > Introduction: AR disorder is the main driver of prostate cancer < br / > representative protac molecules: arcc-4, arv-110 < br / > supplementary information: in October 2019, arvinas company, founded by Professor Craig crews, a pioneer of protacs technology, published the preliminary data of arv-110 phase I trial (from 10 patients) The results showed that the three dose groups (35 mg, 70 mg, 140 mg) were well tolerated, no dose limited toxicity, and no grade 2, 3 or 4 related adverse events were observed < br / > target 4: BCL2 < br / > Introduction: BCL2 is classified as a carcinogenic gene because of its important role as an anti apoptotic protein BCL2 disorders can lead to different cancers < br / > representative protocs: C5 < br / > target 5: BCL6 (B-cell lymphama 6) < br / > Introduction: BCL6 has been found to participate in the differentiation and proliferation of diffuse large B-cell lymphoma and follicular lymphoma through multiple gene changes < br / > representative protocs: see figure below < br / > target 6: bcr-abl < br / > Introduction: bcr-abl fusion gene is the main cause of chronic myeloid lymphoma < br / > representative protocs: das-6-2-2-6-crbn, das-iap < br / > target 7: bet (bromodomain and extratamina) < br / > Introduction: it has been confirmed that inhibition of bet family protein can play an anti-cancer role in the pre clinical model of castrated resistant prostate cancer < br / > representative protocs: arv-771, dbet1, bet-246 < br / > target 8: brd9 and BRD7 < br / > Introduction: many cancers including cervical cancer show brd9 overexpression BRD7 is a close homolog of brd9 < br / > representative protocs molecules: dbrd9, vz185 < br / > target 9: Btk < br / > Introduction: B cell receptor (BCR) is an important regulator in B cell adhesion, survival and growth signal pathway, and in BCR pathway, Btk is essential < br / > representative protocs: l18i, mt-802, dd-03-171, etc < br / > target 10: CDK4 / 6 (cyclin dependent kinases 4 and 6) < br / > Introduction: CDK4 / 6 is a key regulator of cell cycle, and plays a key role in the transition from G1 to S-phase CDK4 / 6 is overactive in many cancers, resulting in uncontrolled cell proliferation < br / > representative protocs: bsj-03-204, bsj-04-132, bsj-03-123, CP-10, etc < br / > target 11: Cdk8 (cyclin dependent kinase 8) < br / > Introduction: Cdk8 gene overexpression destroys cell proliferation, differentiation and apoptosis, and can accelerate the growth and division of cancer cells, such as cervical cancer, colorectal cancer, gastric cancer, malignant melanoma, etc < br / > representative protocs: jh-xi-10-02 < br / > target 12: CDK9 (cyclin dependent kinase 9) < br / > Introduction: CDK9 is widely expressed in a variety of malignant tumors < br / > representative protocs: the-sns-032 et al < br / > target 13: CK2 (casein kinase 2) < br / > Introduction: CK2 overexpression is related to the occurrence of cancer < br / > representative protocs: see figure below < br / > target 14: c-met < br / > Introduction: c-met is related to cancer cell survival, growth, angiogenesis and metastasis < br / > representative protocs: see the figure below < br / > target 15: DHODH (dihydroorganic dehydrogenase) < br / > Introduction: DHODH provides the basis for further synthesis of RNA, DNA, glycoprotein and phospholipid Inhibition of DHODH activity has been considered as a promising therapeutic strategy against viral infection, cancer, arthritis and immunosuppression < br / > representative protocs: see figure below < br / > target 16: EGFR and HER2 < br / > Introduction: EGFR (epigermal growth factor receptor) over expression plays an important role in the development of malignant tumors, such as glioblastoma, NSCLC, head and neck cancer, breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, etc HER2 is one of the four members of the EGFR family < br / > representative protocs: see the figure below < br / > target 17: eIF4E (eukaryotic translation initiation factor 4E) < br / > Introduction: eIF4E has an important influence on cell proliferation, differentiation and metastasis Studies have shown that eIF4E is overexpressed in many animal and human malignant cell lines and primary tumors < br / > representative protocs: see the figure below < br / > target 18: Er < br / > Introduction: 80% of newly diagnosed breast cancer cases are Er α positive < br / > representative protocs: arv-471, etc < br / > target 19: ERK1 and ERK2 < br / > Introduction: ERK1 and ERK2 participate in RAS-RAF-MEK-ERK signal transduction cascade, while RAS-RAF-MEK-ERK signal pathway is related to a variety of cancers < br / > representative protocs: ERK cliptac et al < br / > target 20: err α (estimated related receptors) < br / > Introduction: errs plays an important role in maintaining homeostasis, including the metabolic balance related to err α and err γ < br / > representative protocs molecule: protoc_ Err α et al < br / > target 21: FAK (focal adhesion kinase) < br / > Introduction: FAK has kinase dependent enzyme function and non kinase dependent stent function, which play an important role in the development of cancer < br / > representative protocs: bi-3663, bi-0319, fc-11, etc < br / > target 22: Flt-3 (FMS like tyrosine kinase 3) < br / > Introduction: FLT3 plays an important role in cell proliferation, differentiation and apoptosis About 30% of newly diagnosed AML patients have FLT3 mutation < br / > representative protocs: tl13-117, tl13-149, etc < br / > target 23: HDAC6 (histone deacetylases) < br / > Introduction: HDAC6 belongs to type II histone deacetylase (HDAC) family, with unique structure and biological characteristics More and more studies show that HDAC6 is closely related to the occurrence and development of tumor < br / > representative protocs molecules: see the figure below < br / > target 24: MCL1 (myeloid cell leukemia 1) < br / > Introduction: MCL1 is a survival promoting protein overexpressed in a variety of different cancers, such as lymphoma, leukemia, breast cancer < br / > representative protocs: dmcl1-2 et al < br / > target 25: MDM2 (murine double minute 2) < br / > Introduction: MDM2 is a negative endogenous regulator of p53 MDM2 is overexpressed in some human wild-type p53 cancers < br / > representative protocs: md-224 et al < br / > target 26: p38 α and p38 δ < br / > Introduction: p38 MAPK kinase can be activated by various cell pressures and inflammatory cytokines, which is composed of p38 α, p38 β, p38 γ and p38 δ < br / > representative protocs: SJF α, SJF δ < br / > target 27: PARP1 (poly (ADP ribose) polymers) < br / > Introduction: because of the key role of PARP1 in DNA damage response, it is considered as a powerful cancer treatment target < br / > representative protocs molecules: see the figure below < br / > target 28: PI3K (phosphoroside 3-kinases) < br / > Introduction: overexpression of P13K dependent signaling pathway is one of the main characteristics of tumorigenesis < br / > representative protocs: see figure below < br / > target 29: Pirin < br / > Introduction: Pirin has been reported as a transcription factor regulator It has been shown that the removal of Pirin by siRNA can inhibit the migration and proliferation of cancer cells < br / > representative protocs molecules: see the figure below < br / > target 30: PRC2 (Polycomb reactive complex 2) or its core subunit eed (endogenous ectoderm Development) < br / > Introduction: according to reports, PRC2 can be used as both carcinogenic gene and tumor suppressor in various cancer types < br / > representative protocs: unc6852 < br / > target 31: ripk2 < br / > Introduction: serine threonine kinase ripk2 is an important innate immune regulator of Nod1 and NOD2 signals < br / > representative protocs molecule: protoc_ Ripk2 < br / > target 32: Rpn13 < br / > Introduction: Rpn13 is highly expressed in multiple myeloma cells, and plays an important role in the growth and survival of multiple myeloma cells < br / > representative protocs: wl40 < br / > target 33: sgk3 (serum / glycorticoid induced protein kinase) < br / > Introduction: SGK is the key downstream signal molecule of PI3K Sgk-3 is a subtype of SGK family, which plays an important role in cell proliferation and survival, especially in breast cancer, liver cancer, colorectal cancer and prostate cancer < br / > representative protocs: see the figure below < br / > target 34: Smad3 < br / > Introduction: Smad3 expression