E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

Abstract

Bifunctional degrader molecules, also called proteolysis-targeting chimeras (PROTACs), are a new modality of chemical tools and potential therapeutics to understand and treat human disease. A required PROTAC component is a ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded via the ubiquitin-proteasome system. The advent of nonpeptidic small-molecule E3 ligase ligands, notably for von Hippel-Lindau (VHL) and cereblon (CRBN), revolutionized the field and ushered in the design of drug-like PROTACs with potent and selective degradation activity. A first wave of PROTAC drugs are now undergoing clinical development in cancer, and the field is seeking to extend the repertoire of chemistries that allow hijacking new E3 ligases to improve the scope of targeted protein degradation.Here, we briefly review how traditional E3 ligase ligands were discovered, and then outline approaches and ligands that have been recently used to discover new E3 ligases for PROTACs. We will then take an outlook at current and future strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of DNA-encoded libraries (DELs), display technologies and cyclic peptides, smaller molecular glue degraders, and covalent warhead ligands. These approaches are ripe for expanding the chemical space of PROTACs and usher in the advent of other emerging bifunctional modalities of proximity-based pharmacology.

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    Gehringer M. Laufer S. A. Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology. J. Med. Chem. 2019, 62, 5673–5724.

    Not in our library10.1021/acs.jmedchem.8b01153

92. 92.

    Kung W.-W. Ramachandran S. Makukhin N.; et al. Structural Insights into Substrate Recognition by the SOCS2 E3 Ubiquitin Ligase. Nat. Commun. 2019, 10, 2534.

    Not in our library10.1038/s41467-019-10190-4

93. 93.

    Bulatov E. Martin E. M. Chatterjee S.; et al. Biophysical Studies on Interactions and Assembly of Full-Size E3 Ubiquitin Ligase: Suppressor of Cytokine Signaling 2 (SOCS2)-Elongin BC-Cullin 5-Ring Box Protein 2 (RBX2). J. Biol. Chem. 2015, 290, 4178–4191.

    Not in our library10.1074/jbc.m114.616664

94. 94.

    Zadjali F. Pike A. C. Vesterlund M.; et al. Structural Basis for c-KIT Inhibition by the Suppressor of Cytokine Signaling 6 (SOCS6) Ubiquitin Ligase. J. Biol. Chem. 2011, 286, 480–490.

    Not in our library10.1074/jbc.m110.173526

95. 95.

    Zhao B. Payne W. G. Sai J.; et al. Structural Elucidation of Peptide Binding to KLHL-12, a Substrate Specific Adapter Protein in a Cul3-Ring E3 Ligase Complex. Biochemistry. 2020, 59, 964–969.

    Not in our library10.1021/acs.biochem.9b01073

96. 96.

    Rusnac D.-V. Lin H.-C. Canzani D.; et al. Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase. Mol. Cell. 2018, 72, 813–822.e4.

    Not in our library10.1016/j.molcel.2018.10.021

97. 97.

    Chen S.-J. Wu X. Wadas B.; et al. An N-End Rule Pathway That Recognizes Proline and Destroys Gluconeogenic Enzymes. Science. 2017, 355, eaal3655.

    Not in our library10.1126/science.aal3655

98. 98.

    Dong C. Zhang H. Li L.; et al. Molecular Basis of GID4-Mediated Recognition of Degrons for the Pro/N-End Rule Pathway. Nat. Chem. Biol. 2018, 14, 466–473.

    Not in our library10.1038/s41589-018-0036-1

99. 99.

    Carter A. J. Kraemer O. Zwick M.; et al. Target 2035: Probing the Human Proteome. Drug Discov. Today. 2019, 24, 2111–2115.

    Not in our library10.1016/j.drudis.2019.06.020

100. 100.

     Mullard A. A Probe for Every Protein. Nat. Rev. Drug Discov. 2019, 18, 733–736.

     Not in our library10.1038/d41573-019-00159-9

101. 101.

     Goodnow R. A. Jr. Dumelin C. E. Keefe A. D. DNA-Encoded Chemistry: Enabling the Deeper Sampling of Chemical Space. Nat. Rev. Drug Discov. 2017, 16, 131–147.

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102. 102.

     Zambaldo C. Daguer J.-P. Saarbach J.; et al. Screening for Covalent Inhibitors Using DNA-Display of Small Molecule Libraries Functionalized with Cysteine Reactive Moieties. Med. Chem. Commun. 2016, 7, 1340–1351.

     Not in our library

103. 103.

     Chan A. I. McGregor L. M. Jain T.; et al. Discovery of a Covalent Kinase Inhibitor from a DNA-Encoded Small-Molecule Library × Protein Library Selection. J. Am. Chem. Soc. 2017, 139, 10192–10195.

     Not in our library10.1021/jacs.7b04880

104. 104.

     Smith G. P. Phage Display: Simple Evolution in a Petri Dish (Nobel Lecture). Angew. Chem. Int. Ed. 2019, 58, 14428–14437.

     Not in our library10.1002/anie.201908308

105. 105.
     Cyclic and Macrocyclic Peptides as Chemical Tools To Recognise Protein Surfaces and Probe Protein–Protein Interactions · 2015

     No notice
106. 106.

     Dougherty P. G. Qian Z. Pei D. Macrocycles as Protein-Protein Interaction Inhibitors. Biochem. J. 2017, 474, 1109–1125.

     Not in our library10.1042/bcj20160619

107. 107.

     Naylor M. R. Bockus A. T. Blanco M. J.; et al. Cyclic Peptide Natural Products Chart the Frontier of Oral Bioavailability in the Pursuit of Undruggable Targets. Curr. Opin. Chem. Biol. 2017, 38, 141–147.

     Not in our library10.1016/j.cbpa.2017.04.012

108. 108.

     Walport L. J. Obexer R. Suga H. Strategies for Transitioning Macrocyclic Peptides to Cell-Permeable Drug Leads. Curr. Opin. Biotechnol. 2017, 48, 242–250.

     Not in our library10.1016/j.copbio.2017.07.007

109. 109.

     Boehm M. Beaumont K. Jones R.; et al. Discovery of Potent and Orally Bioavailable Macrocyclic Peptide-Peptoid Hybrid CXCR7 Modulators. J. Med. Chem. 2017, 60, 9653–9663.

     Not in our library10.1021/acs.jmedchem.7b01028

110. 110.

     Maianti J. P. McFedries A. Foda Z. H.; et al. Anti-Diabetic Activity of Insulin-Degrading Enzyme Inhibitors Mediated by Multiple Hormones. Nature. 2014, 511, 94–98.

     Not in our library10.1038/nature13297

111. 111.

     Heinis C. Rutherford T. Freund S.; et al. Phage-Encoded Combinatorial Chemical Libraries Based on Bicyclic Peptides. Nat. Chem. Biol. 2009, 5, 502–507.

     Not in our library10.1038/nchembio.184

112. 112.

     Zorzi A. Deyle K. Heinis C. Cyclic Peptide Therapeutics: Past, Present and Future. Curr. Opin. Chem. Biol. 2017, 38, 24–29.

     Not in our library10.1016/j.cbpa.2017.02.006

113. 113.

     Huang Y. Wiedmann M. M. Suga H. RNA Display Methods for the Discovery of Bioactive Macrocycles. Chem. Rev. 2019, 119, 10360–10391.

     Not in our library10.1021/acs.chemrev.8b00430

114. 114.

     McAllister T. E. Yeh T.-L. Abboud M. I.; et al. Non-Competitive Cyclic Peptides for Targeting Enzyme-Substrate Complexes. Chem. Sci. 2018, 9, 4569–4578.

     Not in our library10.1039/c8sc00286j

115. 115.

     Nawatha M. Rogers J. M. Bonn S. M.; et al. De Novo Macrocyclic Peptides That Specifically Modulate Lys48-Linked Ubiquitin Chains. Nat. Chem. 2019, 11, 644–652.

     Not in our library10.1038/s41557-019-0278-x

116. 116.

     Yamagishi Y. Shoji I. Miyagawa S.; et al. Natural product-Like Macrocyclic N-Methyl-Peptide Inhibitors against a Ubiquitin Ligase Uncovered from a Ribosome-Expressed De Novo Library. Chem. Biol. 2011, 18, 1562–1570.

     Not in our library10.1016/j.chembiol.2011.09.013

117. 117.

     Owa T. Okauchi T. Yoshimatsu K.; et al. A Focused Compound Library of Novel N-(7-Indolyl)benzenesulfonamides for the Discovery of Potent Cell Cycle Inhibitors. Bioorg. Med. Chem. Lett. 2000, 10, 1223–1226.

     Not in our library10.1016/s0960-894x(00)00219-5

118. 118.

     Słabicki M. Kozicka Z. Petzold G.; et al. The CDK Inhibitor CR8 Acts as a Molecular Glue Degrader That Depletes Cyclin K. Nature. 2020, 585, 293–297.

     Not in our library10.1038/s41586-020-2374-x

119. 119.

     Mayor-Ruiz C. Bauer S. Brand M.; et al. Rational Discovery of Molecular Glue Degraders via Scalable Chemical Profiling. Nat. Chem. Biol. 2020, 16, 1199–1207.

     Not in our library10.1038/s41589-020-0594-x

120. 120.

     Brand M. Winter G. E. Stick It to E3s. Nat. Chem. Biol. 2019, 15, 655–656.

     Not in our library10.1038/s41589-019-0312-8

121. 121.

     Gadd M. S. Testa A. Lucas X.; et al. Structural Basis of PROTAC Cooperative Recognition for Selective Protein Degradation. Nat. Chem. Biol. 2017, 13, 514–521.

     Not in our library10.1038/nchembio.2329

122. 122.

     Bondeson D. P. Smith B. E. Burslem G. M.; et al. Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem. Biol. 2018, 25, 78–87.e5.

     Not in our library10.1016/j.chembiol.2017.09.010

123. 123.

     Yip K. M. Fischern N. Paknia E.; et al. Breaking the Next Cryo-EM Resolution Barrier – Atomic Resolution Determination of Proteins! bioRxiv. 2020, 106740..

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124. 124.

     Nakane T. Kotecha A. Sente A.; et al. Single-Particle Cryo-EM at Atomic Resolution. bioRxiv. 2020, 110189..

     Not in our library10.1101/2020.05.22.110189

125. 125.

     Senior A. W. Evans R. Jumper J.; et al. Improved Protein Structure Prediction Using Potentials from Deep Learning. Nature. 2020, 577, 706–710.

     Not in our library10.1038/s41586-019-1923-7

126. 126.

     Deshaies R. J. Multispecific Drugs Herald a New Era of Biopharmaceutical Innovation. Nature. 2020, 580, 329–338.

     Not in our library10.1038/s41586-020-2168-1

127. 127.

     Maniaci C. Ciulli A. Bifunctional Chemical Probes Inducing Protein-Protein Interactions. Curr. Opin. Chem. Biol. 2019, 52, 145–156.

     Not in our library10.1016/j.cbpa.2019.07.003

128. 128.

     Whitworth C. Ciulli A. New Class of Molecule Targets Proteins outside Cells for Degradation. Nature. 2020, 584, 193–194.

     Not in our library10.1038/d41586-020-02211-w

129. 129.

     Cornella-Taracido I. Garcia-Echeverria C. Monovalent Protein-Degraders – Insights and Future Perspectives. Bioorg. Med. Chem. Lett. 2020, 30, 127202.

     Not in our library10.1016/j.bmcl.2020.127202

130. 130.

     Hanan E. J. Liang J. Wang X.; et al. Monomeric Targeted Protein Degraders. J. Med. Chem. doi:. https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00093.

     Not in our library10.1021/acs.jmedchem.0c00093

131. 131.

     Takahashi D. Moriyama J. Nakamura T.; et al. AUTACs: Cargo-Specific Degraders Using Selective Autophagy. Mol. Cell. 2019, 76, 797–810.e10.

     Not in our library10.1016/j.molcel.2019.09.009

132. 132.

     Lim S. Khoo R. Peh K. M.; et al. BioPROTACs as Versatile Modulators of Intracellular Therapeutic Targets Including Proliferating Cell Nuclear Antigen (PCNA). Proc. Natl. Acad. Sci. U.S.A. 2020, 117, 5791–5800.

     Not in our library10.1073/pnas.1920251117

133. 133.

     Banik S. M. Pedram K. Wisnovsky S.; et al. Lysosome-Targeting Chimaeras for Degradation of Extracellular Proteins. Nature. 2020, 584, 291–297.

     Not in our library10.1038/s41586-020-2545-9

134. 134.

     Li Z. Wang C. Wang Z.; et al. Allele-Selective Lowering of Mutant HTT Protein by HTT-LC3 Linker Compounds. Nature. 2019, 575, 203–209.

     Not in our library10.1038/s41586-019-1722-1

135. 135.

     Yamazoe S. Tom J. Fu Y.; et al. Heterobifunctional Molecules Induce Dephosphorylation of Kinases – A Proof of Concept Study. J. Med. Chem. 2020, 63, 2807–2813.

     Not in our library10.1021/acs.jmedchem.9b01167

136. 136.

     Siriwardena S. U. Munkanatta Godage D. N. P. Shoba V. M.; et al. Phosphorylation-Inducing Chimeric Small Molecules. J. Am. Chem. Soc. 2020, 142, 14052–14057.

     Not in our library10.1021/jacs.0c05537

137. 137.

     Han X. Zhao L. Xiang W.; et al. Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. J. Med. Chem. 2019, 62, 11218–11231.

     Not in our library10.1021/acs.jmedchem.9b01393

138. 138.

     Farnaby W. Koegl M. Roy M. J.; et al. BAF Complex Vulnerabilities in Cancer Demonstrated via Structure-Based PROTAC Design. Nat. Chem. Biol. 2019, 15, 672–680.

     Not in our library10.1038/s41589-019-0294-6

139. 139.

     Qin C. Hu Y. Zhou B.; et al. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression. J. Med. Chem. 2018, 61, 6685–6704.

     Not in our library10.1021/acs.jmedchem.8b00506

140. 140.

     Rana S. Bendjennat M. Kour S.; et al. Selective Degradation of CDK6 by a Palbociclib Based PROTAC. Bioorg. Med. Chem. Lett. 2019, 29, 1375–1379.

     Not in our library10.1016/j.bmcl.2019.03.035

141. 141.

     Li Z. Pinch B. J. Olson C. M.; et al. Development and Characterization of a Wee1 Kinase Degrader. Cell Chem. Biol. 2020, 27, 57–65.e9.

     Not in our library10.1016/j.chembiol.2019.10.013

142. 142.

     Bensimon A. Pizzagalli M. D. Kartnig F.; et al. Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis. Cell Chem. Biol. 2020, 27, 728–739.e9.

     Not in our library10.1016/j.chembiol.2020.04.003

143. 143.

     Crew A. P. Snyder L. B. Wang J. Compounds and Methods for the Targeted Degradation of Androgen Receptor. U.S. Patent 10,584,101, 3 10, 2020.

     Not in our library

144. 144.

     Mainolfi N. Ji N. Kluge A. F.; et al. IRAK Degraders and Uses Thereof. World Intellectual Property Organization 2019/133531, 7 4, 2019.

     Not in our library

145. 145.

     Qi J. Acetylation Writer Inhibitor Development and Uses Thereof. World Intellectual Property Organization 2020/092907, 5 7, 2019.

     Not in our library

146. 146.

     Yamazaki R. Ibuki T. Sawaguchi Y.; et al. Amide Compound Having BET Proteolysis-Inducing Action and Medicinal Application Thereof. World Intellectual Property Organization 2020/009176, 1 9, 2020.

     Not in our library

147. 147.

     Dragovich P. Pillow T. Blake R. A.; et al. Conjugated Chemical Inducers of Degradation and Methods of Use. World Intellectual Property Organization 2020/086858, 4 30, 2020.

     Not in our library

148. 148.

     Hines J. Lartigue S. Dong H.; et al. MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53. Cancer Res. 2019, 79, 251–262.

     Not in our library10.1158/0008-5472.can-18-2918

149. 149.

     Zhao Q. Lan T. Su S.; et al. Induction of Apoptosis in MDA-MB-231 Breast Cancer Cells by a PARP1-Targeting PROTAC Small Molecule. Chem. Commun. (Camb). 2019, 55, 369–372.

     Not in our library10.1039/c8cc07813k

150. 150.

     Zambaldo C. Vinogradova E. V. Qi X.; et al. 2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles. J. Am. Chem. Soc. 2020, 142, 8972–8979.

     Not in our library10.1021/jacs.0c02721

151. 151.

     Cal P. M. S. D. Vicente J. B. Pires E.; et al. Iminoboronates: A New Strategy for Reversible Protein Modification. J. Am. Chem. Soc. 2012, 134, 10299–10305.

     Not in our library10.1021/ja303436y

152. 152.

     Lin S. Yang X. Jia S.; et al. Redox-Based Reagents for Chemoselective Methionine Bioconjugation. Science. 2017, 355, 597–602.

     Not in our library10.1126/science.aal3316

153. 153.

     Muñoz-Escobar J. Matta-Camacho E. Cho C.; et al. Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase. Structure. 2017, 25, 719–729.e3.

     Not in our library10.1016/j.str.2017.03.004

154. 154.

     Ostertag M. S. Hutwelker W. Plettenburg O.; et al. Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants. J. Mol. Biol. 2019, 431, 2213–2221.

     Not in our library10.1016/j.jmb.2019.04.017

155. 155.

     Ostertag M. S. Messias A. C. Sattler M.; et al. The Structure of the SPOP-Pdx1 Interface Reveals Insights into the Phosphorylation-Dependent Binding Regulation. Structure. 2019, 27, 327–334.e3.

     Not in our library10.1016/j.str.2018.10.005

156. 156.

     Schumacher F.-R. Sorrell F. J. Alessi D. R.; et al. Structural and Biochemical Characterization of the KLHL3-WNK Kinase Interaction Important in Blood Pressure Regulation. Biochem. J. 2014, 460, 237–246.

     Not in our library10.1042/bj20140153

157. 157.

     Chen Z. Picaud S. Filippakopoulos P.; et al. Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase. Structure. 2019, 27, 1395–1404.e4.

     Not in our library10.1016/j.str.2019.06.005

158. 158.

     Filippakopoulos P. Low A. Sharpe T. D.; et al. Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4. J. Mol. Biol. 2010, 401, 389–402.

     Not in our library10.1016/j.jmb.2010.06.017

159. 159.

     You T. Wang Y. Li K.; et al. Crystal Structure of SPSB2 in Complex with a Rational Designed RGD-Containing Cyclic Peptide Inhibitor of SPSB2-iNOS Interaction. Biochem. Biophys. Res. Commun. 2017, 489, 346–352.

     Not in our library10.1016/j.bbrc.2017.05.122

160. 160.

     Sadek M. M. Barlow N. Leung E. W. W.; et al. A Cyclic Peptide Inhibitor of the iNOS-SPSB Protein-Protein Interaction as a Potential Anti-Infective Agent. ACS Chem. Biol. 2018, 13, 2930–2938.

     Not in our library10.1021/acschembio.8b00561

161. 161.

     Zeng Z. Wang W. Yang Y.; et al. Structural Basis of Selective Ubiquitination of TRF1 by SCFFbx4. Dev. Cell. 2010, 18, 214–225.

     Not in our library10.1016/j.devcel.2010.01.007

162. 162.

     Li Y. Jin K. Bunker E.; et al. Structural Basis of the Phosphorylation-Independent Recognition of Cyclin D1 by the SCFFBXO31 Ubiquitin Ligase. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, 319–324.

     Not in our library10.1073/pnas.1708677115

163. 163.

     Wu G. Xu G. Schulman B. A.; et al. Structure of a Beta-TrCP1-Skp1-Beta-Catenin Complex: Destruction Motif Binding and Lysine Specificity of the SCF(beta-TrCP1) Ubiquitin Ligase. Mol. Cell. 2003, 11, 1445–1456.

     Not in our library10.1016/s1097-2765(03)00234-x

164. 164.

     Hao B. Oehlmann S. Sowa M. E.; et al. Structure of a Fbw7-Skp1-Cyclin E Complex: Multisite-Phosphorylated Substrate Recognition by SCF Ubiquitin Ligases. Mol. Cell. 2007, 26, 131–143.

     Not in our library10.1016/j.molcel.2007.02.022

165. 165.

     Yalla K. Elliott C. Day J. P.; et al. FBXW7 Regulates DISC1 Stability via the Ubiquitin-Proteosome System. Mol. Psychiatry. 2018, 23, 1278–1286.

     Not in our library10.1038/mp.2017.138

166. 166.

     Tian W. Li B. Warrington R.; et al. Structural Analysis of Human Cdc20 Supports Multisite Degron Recognition by APC/C. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 18419–18424.

     Not in our library10.1073/pnas.1213438109

167. 167.

     Sackton K. L. Dimova N. Zeng X.; et al. Synergistic Blockade of Mitotic Exit by Two Chemical Inhibitors of the APC/C. Nature. 2014, 514, 646–649.

     Not in our library10.1038/nature13660

168. 168.

     Janz J. M. Sakmar T. P. Min K. C. A Novel Interaction between Atrophin-Interacting Protein 4 and Beta-p21-Activated Kinase-Interactive Exchange Factor Is Mediated by an SH3 Domain. J. Biol. Chem. 2007, 282, 28893–28903.

     Not in our library10.1074/jbc.m702678200

169. 169.

     Liu Y. Lau J. Li W.; et al. Structural Basis for the Regulatory Role of the PPxY Motifs in the Thioredoxin-Interacting Protein TXNIP. Biochem. J. 2016, 473, 179–187.

     Not in our library10.1042/bj20150830

170. 170.

     Cappadocia L. Mascle X. H. Bourdeau V.; et al. Structural and Functional Characterization of the Phosphorylation-Dependent Interaction between PML and SUMO1. Structure. 2015, 23, 126–138.

     Not in our library10.1016/j.str.2014.10.015

171. 171.

     James L. C. Keeble A. H. Khan Z.; et al. Structural Basis for PRYSPRY-Mediated Tripartite Motif (TRIM) Protein Function. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 6200–6205.

     Not in our library10.1073/pnas.0609174104

172. 172.

     Tsai W.-W. Wang Z. You T. T.; et al. TRIM24 Links a Non-Canonical Histone Signature to Breast Cancer. Nature. 2010, 468, 927–932.

     Not in our library10.1038/nature09542

173. 173.

     Palmer W. S. Poncet-Montange G. Liu G.; et al. Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor. J. Med. Chem. 2016, 59, 1440–1454.

     Not in our library10.1021/acs.jmedchem.5b00405

174. 174.

     Liu J. Li F. Bao H.; et al. The Polar Warhead of a TRIM24 Bromodomain Inhibitor Rearranges a Water-Mediated Interaction Network. FEBS J. 2017, 284, 1082–1095.

     Not in our library10.1111/febs.14041

175. 175.

     Xi Q. Wang Z. Zaromytidou A.-I.; et al. A Poised Chromatin Platform for TGF-β Access to Master Regulators. Cell. 2011, 147, 1511–1524.

     Not in our library10.1016/j.cell.2011.11.032

Cited by papers we hold 6

• Proximity-Based Modalities for Biology and Medicine · 2023
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• Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders · 2022
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• Key Considerations in Targeted Protein Degradation Drug Discovery and Development · 2022
  Not checked
• Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2 · 2022
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• An overview of PROTACs: a promising drug discovery paradigm · 2022
  No notice
• Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function · 2021
  Not checked

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