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- W4225753704 abstract "Criteria for predicting the druglike properties of beyond Rule of 5 Proteolysis Targeting Chimeras (PROTAC) degraders are underdeveloped. PROTAC components are often combined via amide couplings due to their reliability. Amides, however, can give rise to poor absorption, distribution, metabolism, and excretion (ADME) properties. We hypothesized that a bioisosteric amide-to-ester substitution could lead to improvements in both physicochemical properties and bioactivity. Using model compounds, bearing either amides or esters, we identify parameters for optimal lipophilicity and permeability. We applied these learnings to design a set of novel amide-to-ester-substituted, VHL-based BET degraders with the goal to increase permeability. Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect. These enhancements were driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution provides a simple strategy to enhance PROTAC permeability and bioactivity and may prove beneficial to other beyond Ro5 molecules." @default.
- W4225753704 created "2022-05-05" @default.
- W4225753704 creator A5035875633 @default.
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- W4225753704 creator A5041644296 @default.
- W4225753704 creator A5055545423 @default.
- W4225753704 creator A5080207890 @default.
- W4225753704 date "2021-12-09" @default.
- W4225753704 modified "2023-10-15" @default.
- W4225753704 title "Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity" @default.
- W4225753704 cites W1175086522 @default.
- W4225753704 cites W1488181101 @default.
- W4225753704 cites W1512690422 @default.
- W4225753704 cites W1565539350 @default.
- W4225753704 cites W1979189217 @default.
- W4225753704 cites W1990174038 @default.
- W4225753704 cites W2000219706 @default.
- W4225753704 cites W2002111767 @default.
- W4225753704 cites W2008015262 @default.
- W4225753704 cites W2032865438 @default.
- W4225753704 cites W2041535798 @default.
- W4225753704 cites W2051883847 @default.
- W4225753704 cites W2062458432 @default.
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- W4225753704 cites W2065601090 @default.
- W4225753704 cites W2065889205 @default.
- W4225753704 cites W2068455168 @default.
- W4225753704 cites W2070845341 @default.
- W4225753704 cites W2079241230 @default.
- W4225753704 cites W2087979964 @default.
- W4225753704 cites W2090958270 @default.
- W4225753704 cites W2095500337 @default.
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- W4225753704 cites W2102479939 @default.
- W4225753704 cites W2104016565 @default.
- W4225753704 cites W2106605095 @default.
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- W4225753704 cites W2136359146 @default.
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- W4225753704 cites W2155958514 @default.
- W4225753704 cites W2227431445 @default.
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- W4225753704 cites W2597078857 @default.
- W4225753704 cites W2623602792 @default.
- W4225753704 cites W2751709490 @default.
- W4225753704 cites W2767856718 @default.
- W4225753704 cites W2767966404 @default.
- W4225753704 cites W2769590617 @default.
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- W4225753704 cites W2938148420 @default.
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- W4225753704 cites W2945072593 @default.
- W4225753704 cites W2948220248 @default.
- W4225753704 cites W2968014120 @default.
- W4225753704 cites W2968714973 @default.
- W4225753704 cites W2980052892 @default.
- W4225753704 cites W2985526712 @default.
- W4225753704 cites W2989702634 @default.
- W4225753704 cites W2996380129 @default.
- W4225753704 cites W2996636067 @default.
- W4225753704 cites W2997841118 @default.
- W4225753704 cites W3016362891 @default.
- W4225753704 cites W3027386205 @default.
- W4225753704 cites W3031756382 @default.
- W4225753704 cites W3034911617 @default.
- W4225753704 cites W3036496153 @default.
- W4225753704 cites W3046518781 @default.
- W4225753704 cites W3046562742 @default.
- W4225753704 cites W3046939357 @default.
- W4225753704 cites W3117557114 @default.
- W4225753704 cites W3128148409 @default.
- W4225753704 cites W3130894852 @default.
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- W4225753704 doi "https://doi.org/10.1021/acs.jmedchem.1c01496" @default.
- W4225753704 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34881891" @default.
- W4225753704 hasPublicationYear "2021" @default.
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