Rational Approach to Targeting Transcription Factors with Small Molecule Degraders

2019 Emerging Leader Award

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

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.

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.