Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases

A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

“…1 H NMR (400 MHz; CDCl 3 ): δ 7.82 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.19 (t, J = 5.8 Hz, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.48 (s, 3H), 2.05 (quint, J = 5.8 Hz, 2H). 13 4-Isocyanobutyl 4-Methylbenzenesulfonate (17). The title compound was synthesized following the general procedure A.…”

“…1 H NMR (400 MHz; DMSO-d 6 , 353 K): δ 7.77 (t, J = 7.9 Hz, 1H), 7.48−7.44 (m, 5H), 7.43−7.41 (m, 1H), 5.03 (dd, J s = 12.3, 5.4 Hz, 1H), 4.62 (t, J = 6.7 Hz, 1H), 4.24 (t, J = 6.4 Hz, 2H), 4−07−4.03 (m, 1H), 3.68−3.55 (m, 2H), 3.45−3.41 (m, 1H), 3.23 (s, 3H), 3.18 (q, J = 6.4 Hz, 2H), 2.69−2.65 (m, 2H), 2.61 (s, 3H), 2.58−2.57 (m, 1H), 2.43 (s, 3H), 2.12−2.06 (m, 1H), 1.81 (quint, J = 6.4 Hz, 2H), 1.68 (s, 3H), 1.59−1.49 (m, 4H). 13 S3 for NMR spectra of compound 24. (25).…”

“…1 H NMR (400 MHz; (CD 3 ) 2 CO): δ 10.08 (br s, 1H), 8.22 (br t, J = 6.9 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H), 7.64 (br t, J = 5.8 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.47−7.39 (m, 4H), 5.12 (ddd, J s = 12.6, 5.4, 2.3 Hz, 1H), 4.68 (dd, J s = 8.6, 6.1 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 4.09 (dd, J s = 18.5, 6.7 Hz, 1H), 3.71 (dd, J s = 16.8, 5.0 Hz, 1H), 3.58 (ddd, J s = 15.0, 8.6, 3.4 Hz, 1H), 3.34 (ddd, J s = 14.9, 6.1, 2.0 Hz, 1H), 3.25 (q, J = 6.3 Hz, 2H), 3.01−2.91 (m, 1H), 2.83−2.73 (m, 2H), 2.64 (s, 3H), 2.43 (s, 3H), 2.24−2.19 (m, 1H), 1.83 (quint, J = 6.3 Hz, 2H), 1.71 (s, 3H), 1.58− 1.49 (m, 4H). 13 S8 for NMR spectra of compound 29 and Figure S22 for the HPLC chromatogram. (30).…”

“…BET proteins include BRD2, BRD3, BRD4, and BRDT and recruit transcriptional complexes by binding to acetylated lysine residues on histones, thereby controlling genes involved in cellular proliferation and cell cycle progression. Because alterations in the regulation of activities by BET proteins, especially BRD4, 12 are associated with different inflammatory diseases and cancer, several BET degraders, including dBET1, 13 MZ1, 14 dBET21, 15,16 and ARV-771 17 (Figure 3) bearing (+)-JQ1 18,19 as a warhead, have been developed, with the ultimate goal of finding more effective treatments compared to small-molecule inhibitors. 18−20 From a structural point of view, while a large variety of warheads have been explored to bind different POIs, independently from their mechanism of action, cereblon (CRBN) targeting ligands (i.e., immunomodulatory imide drug (IMiD)-based ligands, such as thalidomide and its structural analogues) 21 and Von Hippel-Lindau (VHL) targeting ligands (i.e., hydroxyproline-based molecules) are the most commonly used anchors to recruit E3 ligases (Figure 1).…”

The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation

“…25 Interesting this protein was shown to be upregulated with treatment of the BET inhibitor alone indicating its levels were sensitive to both inhibition and degradation. 25 Additionally, different cell types, which will vary in endogenous expression of target as well as all the E3 ligase machinery 50 needed for degradation likely have different kinetic recovery profiles. Other factors which can greatly influence recovery are compound stability and/or rate of compound efflux.…”