Fangfang Shen

All Publications

• Opportunities and challenges of protein-based targeted protein degradation. Chemical science Shen, F., Dassama, L. M. 2023; 14 (32): 8433-8447

  Abstract

  In the 20 years since the first report of a proteolysis targeting chimeric (PROTAC) molecule, targeted protein degradation (TPD) technologies have attempted to revolutionize the fields of chemical biology and biomedicine by providing exciting research opportunities and potential therapeutics. However, they primarily focus on the use of small molecules to recruit the ubiquitin proteasome system to mediate target protein degradation. This then limits protein targets to cytosolic domains with accessible and suitable small molecule binding pockets. In recent years, biologics such as proteins and nucleic acids have instead been used as binders for targeting proteins, thereby expanding the scope of TPD platforms to include secreted proteins, transmembrane proteins, and soluble but highly disordered intracellular proteins. This perspective summarizes the recent TPD platforms that utilize nanobodies, antibodies, and other proteins as binding moieties to deplete challenging targets, either through the ubiquitin proteasome system or the lysosomal degradation pathway. Importantly, the perspective also highlights opportunities and remaining challenges of current protein-based TPD technologies.

  View details for DOI 10.1039/d3sc02361c

  View details for PubMedID 37592990

  View details for PubMedCentralID PMC10430753

• A Cell-Permeant Nanobody-Based Degrader That Induces Fetal Hemoglobin. ACS central science Shen, F., Zheng, G., Setegne, M., Tenglin, K., Izadi, M., Xie, H., Zhai, L., Orkin, S. H., Dassama, L. M. 2022; 8 (12): 1695-1703

  Abstract

  Proximity-based strategies to degrade proteins have enormous therapeutic potential in medicine, but the technologies are limited to proteins for which small molecule ligands exist. The identification of such ligands for therapeutically relevant but "undruggable" proteins remains challenging. Herein, we employed yeast surface display of synthetic nanobodies to identify a protein ligand selective for BCL11A, a critical repressor of fetal globin gene transcription. Fusion of the nanobody to a cell-permeant miniature protein and an E3 adaptor creates a degrader that depletes cellular BCL11A in differentiated primary erythroid precursor cells, thereby inducing the expression of fetal hemoglobin, a modifier of clinical severity of sickle cell disease and β-thalassemia. Our strategy provides a means of fetal hemoglobin induction through reversible, temporal modulation of BCL11A. Additionally, it establishes a new paradigm for the targeted degradation of previously intractable proteins.

  View details for DOI 10.1021/acscentsci.2c00998

  View details for PubMedID 36589886

  View details for PubMedCentralID PMC9801508

• Mediating K+/H+ Transport on Organelle Membranes to Selectively Eradicate Cancer Stem Cells with a Small Molecule. Journal of the American Chemical Society Shen, F. F., Dai, S. Y., Wong, N. K., Deng, S., Wong, A. S., Yang, D. 2020; 142 (24): 10769-10779

  Abstract

  Molecules that are capable of disrupting cellular ion homeostasis offer unique opportunities to treat cancer. However, previously reported synthetic ion transporters showed limited value, as promiscuous ionic disruption caused toxicity to both healthy cells and cancer cells indiscriminately. Here we report a simple yet efficient synthetic K+ transporter that takes advantage of the endogenous subcellular pH gradient and membrane potential to site-selectively mediate K+/H+ transport on the mitochondrial and lysosomal membranes in living cells. Consequent mitochondrial and lysosomal damages enhanced cytotoxicity to chemo-resistant ovarian cancer stem cells (CSCs) via apoptosis induction and autophagy suppression with remarkable selectivity (up to 47-fold). The eradication of CSCs blunted tumor formation in mice. We believe this strategy can be exploited in the structural design and applications of next-generation synthetic cation transporters for the treatment of cancer and other diseases related to dysfunctional K+ channels.

  View details for DOI 10.1021/jacs.0c02134

  View details for PubMedID 32441923

• A small synthetic molecule functions as a chloride-bicarbonate dual-transporter and induces chloride secretion in cells CHEMICAL COMMUNICATIONS Liu, P., Li, S., Shen, F., Ko, W., Yao, X., Yang, D. 2016; 52 (46): 7380–83

  Abstract

  A C2 symmetric small molecule composed of l-phenylalanine and isophthalamide was found to function as a Cl(-)/HCO3(-) dual transporter and self-assemble into chloride channels. In Ussing-chamber based short-circuit current measurements, this molecule elicited chloride-dependent short-circuit current (Isc) increase in both Calu-3 cell and CFBE41o-cell (with F508del mutant CFTR) monolayers.

  View details for DOI 10.1039/c6cc01964a

  View details for Web of Science ID 000378003100013

  View details for PubMedID 27188496

• Catalytic Asymmetric 1,2-Addition of alpha-Isothiocyanato Phosphonates: Synthesis of Chiral beta-Hydroxy- or beta-Amino-Substituted alpha-Amino Phosphonic Acid Derivatives ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Cao, Y., Shen, F., Zhang, F., Zhang, J., Wang, R. 2014; 53 (7): 1862–66

  Abstract

  α-Amino phosphonic acid derivatives are considered to be the most important structural analogues of α-amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2-addition reactions of α-isothiocyanato phosphonate were developed. Through these processes, derivatives of β-hydroxy-α-amino phosphonic acid and α,β-diamino phosphonic acid, as well as highly functionalized phosphonate-substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α-phosphonic acid derivatives.

  View details for DOI 10.1002/anie.201308514

  View details for Web of Science ID 000330680400020

  View details for PubMedID 24420101

• Catalytic Enantioselective Ring-Opening Reaction of meso-Aziridines with -Isothiocyanato Imides CHEMISTRY-A EUROPEAN JOURNAL Cao, Y., Zhang, F., Shen, F., Wang, R. 2013; 19 (29): 9476–80

  View details for DOI 10.1002/chem.201300297

  View details for Web of Science ID 000321431600015

  View details for PubMedID 23749677

• Catalytic Asymmetric Michael Addition/Cyclization of Isothiocyanato Oxindoles: Highly Efficient and Versatile Approach for the Synthesis of 3,2'-Pyrrolidinyl Mono- and Bi-spirooxindole Frameworks CHEMISTRY-A EUROPEAN JOURNAL Cao, Y., Shen, F., Zhang, F., Wang, R. 2013; 19 (4): 1184–88

  View details for DOI 10.1002/chem.201204114

  View details for Web of Science ID 000313721500005

  View details for PubMedID 23255227

• Enantioselective Michael/Cyclization Reaction Sequence: Scaffold-Inspired Synthesis of Spirooxindoles with Multiple Stereocenters ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Cao, Y., Jiang, X., Liu, L., Shen, F., Zhang, F., Wang, R. 2011; 50 (39): 9124–27

  View details for DOI 10.1002/anie.201104216

  View details for Web of Science ID 000296104300020

  View details for PubMedID 21919145

• A Unique Approach to the Concise Synthesis of Highly Optically Active Spirooxazolines and the Discovery of a More Potent Oxindole-Type Phytoalexin Analogue JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Jiang, X., Cao, Y., Wang, Y., Liu, L., Shen, F., Wang, R. 2010; 132 (43): 15328–33

  Abstract

  Drug-lead synthesis through rapid construction of chiral molecular complexity around the biologically relevant framework using a highly efficient strategy is a key goal of organic synthesis. Molecules bearing a spirooxindole-type framework exhibit important bioactivities. Herein, we present a highly efficient and convenient strategy that allows rapid construction of unique optically active spiro[oxazoline-3,3'-oxindole]s through the organocatalyzed asymmetric synthesis of spirocyclic thiocarbamates via an aldol reaction. Preliminary biological evaluation of several of the spirooxazolines using a model of acute neuroinflammation revealed promising antipyretic activity and provided an opportunity to discover new antipyretic agents.

  View details for DOI 10.1021/ja106349m

  View details for Web of Science ID 000283621700046

  View details for PubMedID 20939568

• Direct Organocatalytic Asymmetric Aldol Reaction of alpha-Isothiocyanato Imides to alpha-Ketoesters under Low Ligand Loading: A Doubly Stereocontrolled Approach to Cyclic Thiocarbamates Bearing Chiral Quaternary Stereocenters ORGANIC LETTERS Jiang, X., Zhang, G., Fu, D., Cao, Y., Shen, F., Wang, R. 2010; 12 (7): 1544–47

  Abstract

  The first doubly stereocontrolled organocatalytic asymmetric aldol reaction of alpha-isothiocyanato imides with alpha-ketoesters by using rosin-derived tertiary amine-thiourea under low ligand loading to form cyclic thiocarbamates bearing quaternary stereogenic centers with high levels of enantio- and diastereoselectivity (up to 99% ee, and 97:3 dr) is presented. This reaction provides a convenient doubly stereocontrolled method to access synthetic useful multiply substituted cyclic thiocarbamates with high optical purity.

  View details for DOI 10.1021/ol1002829

  View details for Web of Science ID 000275885400043

  View details for PubMedID 20205429