Monoclonal antibody (MoAb) for cancer treatment has been greatly progressed during this decade. Six kinds of MoAbs are now in clinical use in Japan. Here we review on the development of MoAbs such as rituximab, bevacizumab and cetuximab. The characterization and the nomenclature of MoAb are also described. Panitumumab, a new MoAb targeting epithelial growth factor receptor(EGFR), and the resistance of colorectal cancer with KRAS mutation for anti-EGFR MoAbs are on recent topics. The concept of bevacizumab beyond progression (BBP) and the unfavorable results of bevacizumab in elder nonsmall cell lung carcinoma patients are so suggestive considering the strategy of the individualized cancer therapy. Finally, "drug lag" for the development of anti-cancer agents between Eastern and Western has to be discussed.

Antibody therapy in cancer

There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

Abstract Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs. 

/pdf/proteolysis-targeting-chimeras-protacs-in-cancer-therapy-3qtnp7bw.pdf

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.

The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.

As alternatives to small-molecular proteolysis-targeting chimeras (PROTAC), peptide-based molecular glues (MG) are a broad range of dual-functional ligands that simultaneously bind with targetable proteins and E3 ligases by mimicking proteinprotein interaction (PPI) partners. Methods: Herein, we design a peptide-derived MG to target a tumor-driving protein, MDMX, for degradation, and nanoengineered it into a supramolecular gold(I)-thiol-peptide complex (Nano-MP) to implement the proteolysis recalcitrance, cellular internalization, and glutathione-triggered release. To optimize the tumor targeting, a pH-responsive macromolecule termed polyacryl sulfydryl imidazole (PSI) was synthesized to coat Nano-MP. Results: As expected, Nano-MP@PSI induced the MDMX degradation by ubiquitination and subsequently restored the anti-cancer function of p53 and p73. Nano-MP@PSI revealed potent anti-cancer activities in an orthotopic xenograft mouse model of retinoblastoma by intraocular injection and a patient-derived xenograft model of malignant pancreatic cancer by systemic injection, while maintaining a favorable safety profile and showing a highly favorable clearable profile of excretion from the living body. Conclusion: Collectively, this work not only provided a clinically viable paradigm for the treatment of a wide variety of tumors by multiple administration types, but, more importantly, it bridged the chasm between peptides and PROTACs, and likely reinvigorated the development of peptide-derived proteolysis-targeting chimeras for a great variety of diseases.

A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity.

Cancers remain a threat to human health due to the lack of effective therapeutic strategies. Great effort has been devoted to the discovery of drug targets to treat cancers, but novel oncoproteins still need to be unveiled for efficient therapy. Methods: We show that CREPT is highly expressed in pancreatic cancer and is associated with poor disease-free survival. CREPT overexpression promotes but CREPT deletion blocks colony formation and proliferation of pancreatic cancer cells. To provide a proof of concept for CREPT as a new target for the inhibition of pancreatic cancer, we designed a cell-permeable peptide-based proteolysis targeting chimera (PROTAC), named PRTC, based on the homodimerized leucine-zipper-like motif in the C-terminus domain of CREPT to induce its degradation in vivo. Results: PRTC has high affinity for CREPT, with Kd = 0.34 +/- 0.11 μM and is able to permeate into cells because of the attached membrane-transportable peptide RRRRK. PRTC effectively induces CREPT degradation in a proteasome-dependent manner. Intriguingly, PRTC inhibits colony formation, cell proliferation, and motility in pancreatic cancer cells and ultimately impairs xenograft tumor growth, comparable to the effect of CREPT deletion. Conclusions: PRTC-induced degradation of CREPT leads to inhibition of tumor growth, which is promising for the development of new drugs against pancreatic cancer. In addition, using an interacting motif based on the dimerized structure of proteins may be a new way to design a PROTAC aiming at degrading any protein without known interacting small molecules or peptides.

A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer

CREPT and p15RS, also named RPRD1B and RPRD1A, are RPRD (regulation of nuclear pre-mRNA-domain-containing) proteins containing C-terminal domain (CTD)-interacting domain (CID), which mediates the binding to the CTD of Rpb1, the largest subunit of RNA polymerase II (RNAPII). CREPT and p15RS are highly conserved, with a common yeast orthologue Rtt103. Intriguingly, human CREPT and p15RS possess opposite functions in the regulation of cell proliferation and tumorigenesis. While p15RS inhibits cell proliferation, CREPT promotes cell cycle and tumor growth. Aberrant expression of both CREPT and p15RS was found in numerous types of cancers. At the molecular level, both CREPT and p15RS were reported to regulate gene transcription by interacting with RNAPII. However, CREPT also exerts a key function in the processes linked to DNA damage repairs. In this review, we summarized the recent studies regarding the biological roles of CREPT and p15RS, as well as the molecular mechanisms underlying their activities. Fully revealing the mechanisms of CREPT and p15RS functions will not only provide new insights into understanding gene transcription and maintenance of DNA stability in tumors, but also promote new approach development for tumor diagnosis and therapy.

Current understanding of CREPT and p15RS, carboxy-terminal domain (CTD)-interacting proteins, in human cancers.

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A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer

Current understanding of CREPT and p15RS, carboxy-terminal domain (CTD)-interacting proteins, in human cancers.