Rational Approach to Targeting Transcription Factors with Small Molecule Degraders

2019 Emerging Leader Award

Eric S. Fischer, PhD, Dana-Farber Cancer Institute

Eric Fischer, PhD

Dr. Fischer is exploring a new approach to targeting “undruggable” cancer driver proteins by inducing their complete elimination from tumor cells. This approach will be applied to transcription factors, a class of proteins that control gene expression and help determine the characteristics and behavior of the cell. Because transcription factors are often mutated or mis-expressed in cancer but are difficult to manipulate with existing drugs, Dr. Fischer and his team are devising new drugs that trick a cancer cell into degrading these mutant proteins using the cell’s natural protein degradation pathway. Dr. Fischer, who earned a PhD from the Friedrich Miescher Institute in Switzerland, is Assistant Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Dana-Farber Cancer Institute. Recently, he was appointed to co-lead a new Center for Protein Degradation at the Dana-Farber Cancer Institute.

published research

Słabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Fröhling S, Golub TR, Fischer ES, Thomä NH, Ebert BL. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature. 2020.

Gasic I, Groendyke BJ, Nowak RP, Yuan JC, Kalabathula J, Fischer ES, Gray NS, Mitchison TJ. Tubulin Resists Degradation by Cereblon-Recruiting PROTACs. Cells. 2020.

Wu T, Yoon H, Xiong Y, Dixon-Clarke SE, Nowak RP, Fischer ES. Targeted protein degradation as a powerful research tool in basic biology and drug target discovery. Nat Struct Mol Biol. 2020.

Słabicki M, Yoon H, Koeppel J, Nitsch L, Roy Burman SS, Di Genua C, Donovan KA, Sperling AS, Hunkeler M, Tsai JM, Sharma R, Guirguis A, Zou C, Chudasama P, Gasser JA, Miller PG, Scholl C, Fröhling S, Nowak RP, Fischer ES, Ebert BL. Small-molecule-induced polymerization triggers degradation of BCL6. Nature. 2020.

Donovan KA, Ferguson FM, Bushman JW, Eleuteri NA, Bhunia D, Ryu S, Tan L, Shi K, Yue H, Liu X, Dobrovolsky D, Jiang B, Wang J, Hao M, You I, Teng M, Liang Y, Hatcher J, Li Z, Manz TD, Groendyke B, Hu W, Nam Y, Sengupta S, Cho H, Shin I, Agius MP, Ghobrial IM, Ma MW, Che J, Buhrlage SJ, Sim T, Gray NS, Fischer ES. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell. 2020.

Wang ES, Verano AL, Nowak RP, Yuan JC, Donovan KA, Eleuteri NA, Yue H, Ngo KH, Lizotte PH, Gokhale PC, Gray NS, Fischer ES. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat Chem Biol. 2021 Jun.

Faust TB, Donovan KA, Yue H, Chamberlain PP, Fischer ES. Small-Molecule Approaches to Targeted Protein Degradation. Ann Rev Cancer Bio. 2021.

Zhang W, Roy Burman SS, Chen J, Donovan KA, Cao Y, Shu C, Zhang B, Zeng Z, Gu S, Zhang Y, Li D, Fischer ES, Tokheim C, Shirley Liu X. Machine Learning Modeling of Protein-intrinsic Features Predicts Tractability of Targeted Protein Degradation. Genomics Proteomics Bioinformatics. 2022.

Li J, Wang L, Hahn Q, Nowak RP, Viennet T, Orellana EA, Roy Burman SS, Yue H, Hunkeler M, Fontana P, Wu H, Arthanari H, Fischer ES, Gregory RI. Structural basis of regulated m7G tRNA modification by METTL1-WDR4. Nature. 2023.

Hunkeler M, Jin CY, Fischer ES. Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science. 2023.

Sarott RC, You I, Li YD, Toenjes ST, Donovan KA, Seo P, Ordonez M, Byun WS, Hassan MM, Wachter F, Chouchani ET, Słabicki M, Fischer ES, Ebert BL, Hinshaw SM, Gray NS. Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry. J Am Chem Soc. 2023.