Review
Oncology
Lucia Y. Chen, Sarah Gooding
Summary: Resistance to immunomodulatory drugs (IMiDs) is a major cause of treatment failure in multiple myeloma (MM), and understanding the mechanisms behind this resistance is crucial for guiding treatment decisions. While the CRBN-dependent mechanisms of IMiD resistance are being discovered, additional mechanisms, including resistance within the immune microenvironment, need to be explored.
FRONTIERS IN ONCOLOGY
(2022)
Article
Immunology
Vittoria Massafra, Sofia Tundo, Aline Dietzig, Axel Ducret, Christian Jost, Christian Klein, Roland E. Kontermann, Hendrik Knoetgen, Martin Steegmaier, Andrea Romagnani, Yvonne A. Nagel
Summary: This study explores the potential of targeted protein degradation in tumor cells to enhance T cell effector function, and for the first time investigates the impact of combining a degrader and a TCB in cancer immunotherapy.
JOURNAL OF IMMUNOLOGY
(2021)
Article
Medicine, General & Internal
Joanna Barankiewicz, Anna Szumera-Cieckiewicz, Aleksander Salomon-Perzynski, Paulina Wieszczy, Agata Malenda, Filip Garbicz, Monika Prochorec-Sobieszek, Irena Misiewicz-Krzeminska, Przemyslaw Juszczynski, Ewa Lech-Maranda
Summary: The study found that the expression of CRL4-CRBN complex proteins assessed by immunohistochemistry is associated with the treatment response and prognosis in multiple myeloma patients undergoing immunomodulatory drug therapy. This helps identify patients who are more likely to respond positively to immunomodulatory drug therapy.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Oncology
Grzegorz Charlinski, David H. Vesole, Artur Jurczyszyn
Summary: Immunomodulatory drugs (IMiDs), due to their complex mechanism of actions, are a primary drug class used to treat multiple myeloma (MM). The standard of care currently involves combining IMiDs with corticosteroids and other drugs to improve outcomes in MM patients. Recent clinical trials have shown the effectiveness of newer cereblon inhibitors in MM treatment, even in cases refractory to approved IMiDs.
Article
Chemistry, Medicinal
He Chen, Jing Liu, H. Umit Kaniskan, Wenyi Wei, Jian Jin
Summary: This study presents a general strategy for delivering IMiD-based molecular glues and PROTACs to FOLR1-expressing cancer cells, effectively degrading fusion proteins in cancer cells with the potential to ameliorate toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Nikki R. Kong, Hu Liu, Jianwei Che, Lyn H. Jones
Summary: The study evaluates the effects of physicochemical properties of IMiDs, the phthalimide EM 12, and the candidate drug CC-220 (iberdomide) on lipophilicity, solubility, metabolism, permeability, intracellular bioavailability, and cell-based potency. The insights gained from this study will facilitate the rational property-based design and development of targeted protein degraders in the future.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Cell Biology
Jianzhong Hu, Jamie Jarusiewicz, Guoqing Du, Gisele Nishiguchi, Satoshi Yoshimura, John C. Panetta, Zhenhua Li, Jaeki Min, Lei Yang, Divyabharathi Chepyala, Marisa Actis, Noemi Reyes, Brandon Smart, Ching-Hon Pui, David T. Teachey, Zoran Rankovic, Jun J. Yang
Summary: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The LCK inhibitor dasatinib has shown efficacy against T-ALL, but its effect is temporary. Using the PROTAC approach, researchers developed a series of LCK degraders based on dasatinib, with lead compound SJ11646 exhibiting significant efficiency in cereblon-mediated LCK degradation. SJ11646 showed higher cytotoxicity and prolonged suppression of LCK signaling compared to dasatinib, both in vitro and in vivo. SJ11646 also showed binding affinity to several human kinases, making it a potential therapeutic agent for other cancers.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Review
Oncology
Joanna Barankiewicz, Aleksander Salomon-Perzynski, Irena Misiewicz-Krzeminska, Ewa Lech-Maranda
Summary: Multiple myeloma is a common hematological malignancy that can have a recurrent clinical course. Immunomodulatory drugs have significantly improved the prognosis of patients with multiple myeloma. The use of the CRL4(CRBN) complex's activity for treating multiple myeloma is being explored further.
Article
Biochemistry & Molecular Biology
Habib Bouguenina, Andrea Scarpino, Jack A. O'Hanlon, Justin Warne, Hannah Z. Wang, Laura Chan Wah Hak, Amine Sadok, P. Craig McAndrew, Mark Stubbs, Olivier A. Pierrat, Tamas Hahner, Marc P. Cabry, Yann-Vai Le Bihan, Costas Mitsopoulos, Fernando J. Sialana, Theodoros I. Roumeliotis, Rosemary Burke, Rob L. M. van Montfort, Jyoti Choudhari, Rajesh Chopra, John J. Caldwell, Ian Collins
Summary: This study addresses the challenge of selectivity in PROTACs by leveraging structural insights from known CRL4(CRBN) molecular glue degraders, and demonstrates improved selectivity by using computational modeling. The tools and principles presented in this work are valuable for the development of targeted protein degradation.
Review
Hematology
Sarah Bird, Charlotte Pawlyn
Summary: Immunomodulatory agents (IMiDs) are crucial for the treatment of multiple myeloma and their mechanism of action has been recently elucidated. By binding to the cereblon component of the CRL4CRBN E3 ubiquitin ligase, IMiDs target specific proteins for degradation, leading to cell death. However, resistance to IMiDs therapy is an ongoing challenge that requires further research to improve management and outcomes.
Article
Chemistry, Medicinal
Joshua D. Hansen, Matthew Correa, Matt Alexander, Mark Nagy, Dehua Huang, John Sapienza, Gang Lu, Laurie A. LeBrun, Brian E. Cathers, Weihong Zhang, Yang Tang, Massimo Ammirante, Rama K. Narla, Joseph R. Piccotti, Michael Pourdehnad, Antonia Lopez-Girona
Summary: Acute myeloid leukemia poses a significant clinical challenge with poor survival and high relapse rates. CC-90009, a novel protein degrader targeting GSPT1 for proteasomal degradation, represents a promising therapeutic approach currently in phase 1 clinical development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Multidisciplinary
Lizhao Zhu, Rei Kinjo
Summary: Since the discovery of phenyl azide in 1864, various organic azides have been developed and extensively studied. Azides have found applications as building blocks in organic synthesis, bioorthogonal chemistry, and materials science due to their amenability to a range of reactions. This review summarizes the reactions of main group compounds with azides and focuses on their reaction patterns and mechanisms.
CHEMICAL SOCIETY REVIEWS
(2023)
Review
Chemistry, Medicinal
Harbinder Singh, Devendra K. Agrawal
Summary: Protease-targeted chimeras (PROTACs) are a novel therapeutic approach that utilizes the ubiquitin-proteasome system for targeted protein degradation. PROTACs based on small-molecule inhibitors have several advantages and cereblon-based PROTACs have promising clinical potential.
FUTURE MEDICINAL CHEMISTRY
(2022)
Article
Biotechnology & Applied Microbiology
Li Du, Wei Liu, Flavia Pichiorri, Steven T. Rosen
Summary: This study identified SUMOylation as a potential mechanism regulating lenalidomide resistance in multiple myeloma. Inhibition of SUMOylation can enhance sensitivity to lenalidomide by downregulating IRF4 expression.
CANCER GENE THERAPY
(2023)
Article
Chemistry, Organic
Alexander Garay-Talero, Tales A. C. Goulart, Rafael D. C. Gallo, Roberto do C. Pinheiro, Catalina Hoyos-Orozco, Igor D. Jurberg, Diego Gamba-Sanchez
Summary: An aza-Robinson annulation strategy involving NaOEt-catalyzed conjugate addition of cyclic imides onto vinyl ketones and TfOH-mediated intramolecular aldol condensation has been developed for the synthesis of densely functionalized fused bicyclic amides. The potential use of these amides in the synthesis of alkaloids has been demonstrated by the conversion of appropriate precursors to (+/-)-coniceine and quinolizidine in two additional steps, achieving overall yields of 40% and 44%, respectively.
Review
Biochemistry & Molecular Biology
Zhenyi Hu, Craig M. Crews
Summary: PROTACs are an emerging technology that utilizes the ubiquitin-proteasome system for targeted protein degradation, showing great therapeutic potential in treating diseases. Over the past two decades, significant advancements have been made in PROTAC technology, with an increasing repertoire of targets.
Review
Biotechnology & Applied Microbiology
Miklos Bekes, David R. Langley, Craig M. Crews
Summary: Targeted protein degradation (TPD) is a new therapeutic modality that can tackle disease-causing proteins which are difficult to target with conventional small molecules. PROTAC molecules, utilizing the ubiquitin-proteasome system to degrade target proteins, has achieved clinical proof-of-concept and attracted significant industry activity. Future directions include identifying target classes suitable for TPD, expanding the use of ubiquitin ligases for precision medicine, and extending the modality beyond oncology.
NATURE REVIEWS DRUG DISCOVERY
(2022)
Article
Chemistry, Multidisciplinary
Dhanusha A. Nalawansha, Ke Li, John Hines, Craig M. Crews
Summary: This study introduces a novel approach to induce protein degradation by hijacking a methyl reader:E3 ligase complex, demonstrating nuclear-specific degradation of FKBP12 and BRD2.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Jake C. Swartzel, Michael J. Bond, Andreas P. Pintado-Urbanc, Mehana Daftary, Mackenzie W. Krone, Todd Douglas, Evan J. Carder, Joshua T. Zimmer, Takahiro Maeda, Matthew D. Simon, Craig M. Crews
Summary: The RNA decapping scavenger protein DcpS has been identified as a dependency in acute myeloid leukemia (AML), and its inhibition or knockdown shows antiproliferative effects on AML cells. The non-essential nature of DcpS in normal human hematopoietic cells suggests potential for therapeutic intervention in AML by modulating DcpS activity. JCS-1, a PROTAC developed in this study, effectively degrades DcpS in nanomolar concentrations, offering a new strategy for AML and other DcpS-dependent genetic disorders.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Andrew C. McShan, Christine A. Devlin, Georgia F. Papadaki, Yi Sun, Adam I. Green, Giora I. Morozov, George M. Burslem, Erik Procko, Nikolaos G. Sgourakis
Summary: This study reveals the binding mechanism of tapasin and TAPBPR with MR1 protein, promoting its trafficking and cell surface expression. Unlike MHC-I, TAPBPR can recognize MR1 in a ligand-independent manner and induce similar adaptations to those seen in MHC-I/TAPBPR co-crystal structures. Additionally, TAPBPR can affect the exchange kinetics of noncovalent metabolites with the MR1 groove, serving as a catalyst.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Zhenyi Hu, Po-Han Chen, Wenxue Li, Todd Douglas, John Hines, Yansheng Liu, Craig M. Crews
Summary: Microtubule-associated protein tau is crucial for microtubule assembly and stabilization. Tau hyperphosphorylation is implicated in the development of Alzheimer's disease and tauopathies. In this study, we used small molecule-based PhosTACs to induce efficient and sustained tau dephosphorylation by recruiting tau to PP2A, a native tau phosphatase. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. Our findings suggest that PhosTACs represent a potential avenue for disease-modifying therapies for tauopathies.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Review
Oncology
Deborah Chirnomas, Keith R. Hornberger, Craig M. Crews
Summary: Protein degraders are a novel therapeutic modality that selectively target disease-associated proteins for elimination. They have advantages over traditional small-molecule inhibitors and have shown promising activity as cancer therapies in clinical trials. More evidence is needed, but protein degraders represent a new class of drugs for cancer treatment.
NATURE REVIEWS CLINICAL ONCOLOGY
(2023)
Article
Multidisciplinary Sciences
Yuanhui Sun, Lei Zhao, Chris J. Pickard, Russell J. Hemley, Yonghao Zheng, Maosheng Miao
Summary: Most metals have simple structures, but undergo complex transitions on compression. First-principles calculations can reproduce observed structures and transitions, but a unified predictive theory is lacking. By analyzing electronic properties, a simple theory shows that the stability of metal structures is governed by electrons in interstitial orbitals and their chemical interactions. This theory provides a basis for understanding and predicting structures in solid compounds and alloys.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yi Sun, Michael C. Young, Claire H. Woodward, Julia N. Danon, Hau Truong, Sagar Gupta, Trenton J. Winters, Joan Font-Burgada, George M. Burslem, Nikolaos G. Sgourakis
Summary: This study created stable MHC-I molecules capable of accepting low-to moderate-affinity peptides through an engineered disulfide bond bridging conserved epitopes. The effects of the disulfide bond on the conformation of the MHC-I structure were characterized using solution NMR. The structure-guided design provides a universal platform for screening antigenic epitope libraries and studying polyclonal TCR repertoires covering highly polymorphic HLA-I allotypes and oligomorphic nonclassical molecules.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yi Sun, Georgia F. Papadaki, Christine A. Devlin, Julia N. Danon, Michael C. Young, Trenton J. Winters, George M. Burslem, Erik Procko, Nikolaos G. Sgourakis
Summary: Immunological chaperones tapasin and TAP binding protein, related (TAPBPR) play key roles in antigenic peptide optimization and quality control of nascent class I major histocompatibility complex (MHC-I) molecules. The polymorphic nature of MHC-I proteins leads to a range of allelic dependencies on chaperones for assembly and cell-surface expression, limiting chaperone-mediated peptide exchange to a restricted set of human leuko-cyte antigen (HLA) allotypes. By studying a chicken TAPBPR ortholog and its interactions with a repertoire of HLA allotypes, this study discovers that TAPBPR orthologs have broader allele specificity in recognizing empty MHC-I and facilitate peptide exchange by maintaining a reservoir of receptive molecules. Mutations in human TAPBPR resembling the chicken sequence are found to enhance HLA-A*01:01 expression and promote peptide exchange. These findings suggest the possibility of engineering polymorphic sites on MHC-I and chaperone surfaces to manipulate their interactions and enable chaperone-mediated peptide exchange on disease-relevant HLA alleles.
Article
Medicine, Research & Experimental
Jian-Gan Ren, Bowen Xing, Kaoshen Lv, Rachel A. O'Keefe, Mengfang Wu, Ruoxing Wang, Kaylyn M. Bauer, Arevik Ghazaryan, George M. Burslem, Jing Zhang, Ryan M. O'Connell, Vinodh Pillai, Elizabeth O. Hexner, Mark R. Philips, Wei Tong
Summary: RAB27B controls the palmitoylation and trafficking of NRAS, and its expression is associated with poor prognosis in AMLs. RAB27B depletion inhibits the growth of CBL-deficient or NRAS-mutant cell lines.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Chemistry, Multidisciplinary
Timothe Maujean, Prakash Kannaboina, Adam I. Green, George M. Burslem
Summary: We developed a simple and rational method to rank lead-likeness of molecules using continuous evaluation functions, which has proven to be competitive against known methods and has helped in selecting promising candidate molecules for epigenetic applications.
CHEMICAL COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Kusal T. G. Samarasinghe, Elvira An, Miriam A. Genuth, Ling Chu, Scott A. Holley, Craig M. Crews
Summary: The second generation transcription factor targeting chimeras (oligoTRAFTACs) were developed to induce the degradation of oncogenic transcription factors, c-Myc and brachyury, and their activity was demonstrated in chordoma cell lines and zebrafish experiments.
RSC CHEMICAL BIOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Ke Li, Craig M. Crews
Summary: PROTACs are a type of molecules with novel event-driven mechanism, offering multiple advantages over traditional inhibitors, such as catalytic nature and targeted protein degradation, which may lead to improved therapeutic outcomes with reduced toxicity. However, further research and development efforts are needed to fully explore their potential.
CHEMICAL SOCIETY REVIEWS
(2022)
Review
Biochemistry & Molecular Biology
Kusal T. G. Samarasinghe, Craig M. Crews
Summary: Protein homeostasis is crucial for maintaining a balanced, healthy environment within cells, but excessive dysregulated proteins can lead to disease. PROTACs and other Targeted Protein Degradation (TPD) strategies are emerging as potential therapeutic modalities for degrading disease-causing proteins, including previously undruggable targets like transcription factors.
CELL CHEMICAL BIOLOGY
(2021)