Structure-Based Design of CBP/EP300 Degraders: When Cooperativity Overcomes Affinity

Overview

Journal JACS Au

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Sep 27

PMID 39328757

Authors

Ivan Cheng-Sanchez

Katherine Gossele

Leonardo Palaferri

Eleen Laul

Gionata Riccabella

Rajiv K Bedi

Yaozong Li

Anna Muller

Ivan Corbeski

Amedeo Caflisch

Cristina Nevado

Affiliations

Soon will be listed here.

Abstract

We present the development of , a structurally novel PROTAC targeting the CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. The design of was based on the crystal structure of an in-house bromodomain (BRD) inhibitor featuring a 3-methyl-cinnoline acetyl-lysine mimic acetyl-lysine mimic discovered by high-throughput fragment docking. Our study shows that, despite its modest binding affinity to CBP/EP300-BRD, 's remarkable protein degradation activity stems from its good cooperativity, which we demonstrate by the characterization of its ternary complex formation both and . Molecular dynamics simulations indicate that in aqueous solvents, this active degrader populates both folded and extended conformations, which are likely to promote cell permeability and ternary complex formation, respectively.

References

Edmondson S, Yang B, Fallan C . Proteolysis targeting chimeras (PROTACs) in 'beyond rule-of-five' chemical space: Recent progress and future challenges. Bioorg Med Chem Lett. 2019; 29(13):1555-1564. DOI: 10.1016/j.bmcl.2019.04.030. View

Bekes M, Langley D, Crews C . PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022; 21(3):181-200. PMC: 8765495. DOI: 10.1038/s41573-021-00371-6. View

Marchand J, Dalle Vedove A, Lolli G, Caflisch A . Discovery of Inhibitors of Four Bromodomains by Fragment-Anchored Ligand Docking. J Chem Inf Model. 2017; 57(10):2584-2597. DOI: 10.1021/acs.jcim.7b00336. View

Majeux N, Scarsi M, Apostolakis J, Ehrhardt C, Caflisch A . Exhaustive docking of molecular fragments with electrostatic solvation. Proteins. 1999; 37(1):88-105. View

Ogryzko V, Schiltz R, Russanova V, Howard B, Nakatani Y . The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996; 87(5):953-9. DOI: 10.1016/s0092-8674(00)82001-2. View

Visel A, Blow M, Li Z, Zhang T, Akiyama J, Holt A . ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature. 2009; 457(7231):854-8. PMC: 2745234. DOI: 10.1038/nature07730. View

Testa A, Hughes S, Lucas X, Wright J, Ciulli A . Structure-Based Design of a Macrocyclic PROTAC. Angew Chem Int Ed Engl. 2019; 59(4):1727-1734. PMC: 7004083. DOI: 10.1002/anie.201914396. View

Durbin A, Wang T, Wimalasena V, Zimmerman M, Li D, Dharia N . EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma. Cancer Discov. 2021; 12(3):730-751. PMC: 8904277. DOI: 10.1158/2159-8290.CD-21-0385. View

Attar N, Kurdistani S . Exploitation of EP300 and CREBBP Lysine Acetyltransferases by Cancer. Cold Spring Harb Perspect Med. 2016; 7(3). PMC: 5334244. DOI: 10.1101/cshperspect.a026534. View

10.

Atilaw Y, Poongavanam V, Nilsson C, Nguyen D, Giese A, Meibom D . Solution Conformations Shed Light on PROTAC Cell Permeability. ACS Med Chem Lett. 2021; 12(1):107-114. PMC: 7812666. DOI: 10.1021/acsmedchemlett.0c00556. View

11.

Vannam R, Sayilgan J, Ojeda S, Karakyriakou B, Hu E, Kreuzer J . Targeted degradation of the enhancer lysine acetyltransferases CBP and p300. Cell Chem Biol. 2021; 28(4):503-514.e12. DOI: 10.1016/j.chembiol.2020.12.004. View

12.

Wilson J, Patel G, Patel C, Brucelle F, Huhn A, Gardberg A . Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor. ACS Med Chem Lett. 2020; 11(6):1324-1329. PMC: 7294707. DOI: 10.1021/acsmedchemlett.0c00155. View

13.

Huang D, Luthi U, Kolb P, Cecchini M, Barberis A, Caflisch A . In silico discovery of beta-secretase inhibitors. J Am Chem Soc. 2006; 128(16):5436-43. DOI: 10.1021/ja0573108. View

14.

Maple H, Clayden N, Baron A, Stacey C, Felix R . Developing degraders: principles and perspectives on design and chemical space. Medchemcomm. 2019; 10(10):1755-1764. PMC: 6894040. DOI: 10.1039/c9md00272c. View

15.

Thomas 2nd J, Wang M, Jiang W, Wang M, Wang L, Wen B . Discovery of Exceptionally Potent, Selective, and Efficacious PROTAC Degraders of CBP and p300 Proteins. J Med Chem. 2023; 66(12):8178-8199. DOI: 10.1021/acs.jmedchem.3c00492. View

16.

Goossens K, Wroblowski B, Langini C, van Vlijmen H, Caflisch A, De Winter H . Assessment of the Fragment Docking Program SEED. J Chem Inf Model. 2020; 60(10):4881-4893. DOI: 10.1021/acs.jcim.0c00556. View

17.

Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J . CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 2009; 31(4):671-90. PMC: 2888302. DOI: 10.1002/jcc.21367. View

18.

Lai A, Crews C . Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2016; 16(2):101-114. PMC: 5684876. DOI: 10.1038/nrd.2016.211. View

19.

Klein V, Bond A, Craigon C, Lokey R, Ciulli A . Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity. J Med Chem. 2021; 64(24):18082-18101. PMC: 8713283. DOI: 10.1021/acs.jmedchem.1c01496. View

20.

Watanabe T, Seki T, Fukano T, Sakaue-Sawano A, Karasawa S, Kubota M . Genetic visualization of protein interactions harnessing liquid phase transitions. Sci Rep. 2017; 7:46380. PMC: 5390312. DOI: 10.1038/srep46380. View