ELIZA

return kwic search for showed out of >500 occurrences
663834 occurrences (No.9 in the rank) during 5 years in the PubMed. [cache]

290) Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect.

--- ABSTRACT ---

PMID:34881891 DOI:10.1021/acs.jmedchem.1c01496

2021 Journal of medicinal chemistry

* Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity.

- 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.

--- ABSTRACT END ---

[
right
kwic]

[frequency of next (right) word to showed]

(1)197 that	(10)5 higher	(19)3 moderate	(28)2 large
(2)50 a	(11)5 significantly	(20)3 more	(29)2 lower
(3)23 the	(12)4 differential	(21)3 mostly	(30)2 reduced
(4)14 no	(13)4 greater	(22)3 promising	(31)2 remarkable
(5)12 an	(14)4 positive	(23)2 clinically	(32)2 similar
(6)11 significant	(15)3 better	(24)2 efficacy	(33)2 stereoselectivity
(7)6 good	(16)3 extensive	(25)2 hypersensitivity	(34)2 strong
(8)6 high	(17)3 how	(26)2 impairments
(9)5 elevated	(18)3 low	(27)2 increased

add keyword

--- WordNet output for showed --- Overview of verb show The verb show has 12 senses (first 11 from tagged texts) 1. (136) show, demo, exhibit, present, demonstrate -- (give an exhibition of to an interested audience; "She shows her dogs frequently"; "We will demo the new software in Washington") 2. (63) prove, demonstrate, establish, show, shew -- (establish the validity of something, as by an example, explanation or experiment; "The experiment demonstrated the instability of the compound"; "The mathematician showed the validity of the conjecture") 3. (57) testify, bear witness, prove, evidence, show -- (provide evidence for; "The blood test showed that he was the father"; "Her behavior testified to her incompetence") 4. (43) show -- (make visible or noticeable; "She showed her talent for cooking"; "Show me your etchings, please") 5. (32) picture, depict, render, show -- (show in, or as in, a picture; "This scene depicts country life"; "the face of the child is rendered with much tenderness in this painting") 6. (24) express, show, evince -- (give expression to; "She showed her disappointment") 7. (24) indicate, point, designate, show -- (indicate a place, direction, person, or thing; either spatially or figuratively; "I showed the customer the glove section"; "He pointed to the empty parking space"; "he indicated his opponents") 8. (11) show, show up -- (be or become visible or noticeable; "His good upbringing really shows"; "The dirty side will show") 9. (7) read, register, show, record -- (indicate a certain reading; of gauges and instruments; "The thermometer showed thirteen degrees below zero"; "The gauge read `empty'") 10. (6) show -- (give evidence of, as of records; "The diary shows his distress that evening") 11. (2) usher, show -- (take (someone) to their seats, as in theaters or auditoriums; "The usher showed us to our seats") 12. show -- (finish third or better in a horse or dog race; "he bet $2 on number six to show") --- WordNet end ---