Correction to “Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors”

Johannes, Jeffrey W.; Bates, Stephanie M.; Beigie, Carl; Belmonte, Matthew A.; Breen, John; Cao, Shenggen; Centrella, Paolo A.; Cuozzo, John W.; Dumelin, Christoph E.; Ferguson, Andrew D.; Habeshian, Sevan; Hargreaves, David; Joubran, Camil; Kazmirski, Steven L.; Keefe, Anthony D.; Lamb, Michelle L.; Lan, Haiye; Li, Yunxia; Ma, Hao; Mlynarski, Scott N.; Packer, Martin J.; Rawlins, Philip; Robbins, Daniel W.; Shen, Haidong; Sigel, Eric A.; Soutter, Holly H.; Su, Nancy; Troast, Dawn M.; Wang, Haiyun; Wickson, Kate; Wu, Chengyan; Zhang, Ying; Zhao, Qiuying; Zheng, Xiaolan; Hird, Alexander W.

doi:10.1021/acsmedchemlett.7b00397

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“…45 Researchers from AstraZeneca and X-Chem reported the identification of an Mcl-1 inhibitor, which was further optimized to a macrocyclic compound based on ligand-protein crystal structures and binding kinetics (Figure1-10, 15-16). 166 Researchers from BMS and Ensemble Therapeutics identified XIAP BIR2 and BIR3 domain inhibitors after screening of macrocycle libraries synthesized by DNA-programmed chemistry. A subsequent bivalent macrocycle library was generated based on the initial screening results and structure based drug design from which the most potent compound was identified.…”

Section: Hit Identificationmentioning

confidence: 99%

“…The original hit was identified from a DNA-encoded linear peptide library; then structure based drug design led to macrocyclization, which showed a 10-fold binding potency improvement over its linear version. 166 3. In traditional small molecule organic synthesis, macrocyclizations usually run in very diluted concentration (sub-mM to mM) to avoid dimer-or polymerization, which is considered a big hurdle of varies macrocyclization reactions.…”

Section: Macrocycles In Drug Discoverymentioning

confidence: 99%

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Efforts to expand chemistry toolbox for DNA-encoded libraries

Jaturapitakkul¹

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List of SchemesChapter 2: Threonine Aldolase Catalyzed on-DNA Aldol Reaction………………………………..…48 Scheme 2-1. (a) Retro-aldol cleavage of threonine, (b) Threonine aldolase catalyzed aldol reaction, and (c) Catalytic cycle……………………………………………………………………………………………….50 Scheme 2-2. Hypothesis on reactivity loss of HP-1c and HP-1m…………………………………………..56 Scheme 2-3. Diversification of β-hydroxy-α-amino acids…………………………………………………..63 Scheme 2-4. Two proposed libraries…………………………………………………………………………64 Chapter 3: on-DNA Macrocyclization Utilizing Intramolecular Benzimidazole Formation………66 Scheme 3-1. Proof of concept tests…………………………………………………………………………..73 Scheme 3-2. Reaction scheme for scoping study…………………………………………………………...74 Scheme 3-3. Optimized on-DNA nitro reduction…………………………………………………………….76 Scheme 3-4. Proposed Libraries……………………………………………………………………………...77 Scheme 3-5. Acid-aldehyde 3-step validation……………………………………………………………….79 Scheme 3-6. Library scheme………………………………………………………………………………….82 Chapter 4: on-DNA Tetrahydroisoquinoline Formation via Pictet-Spengler Reaction……………89 Scheme 4-1. Pictet-Spengler reactions and reaction mechanism…………………………………………90 Scheme 4-2. on-DNA Pictet-Spengler reaction with CjNCS2………………………………………………92 Scheme 4-3. Proposed catalytic pathway of phosphate catalyzed PS reaction………………………….93 Scheme 4-4. Acylation and reductive acylation of the secondary amine………………………………...108 Scheme 4-5. Fluorosulfonate formation and coupling reactions………………………………………….109 Scheme 4-6. Synthetic scheme of potential DELs…………………………………………………………111

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Section: Hit Identificationmentioning

confidence: 99%

Section: Macrocycles In Drug Discoverymentioning

confidence: 99%

Efforts to expand chemistry toolbox for DNA-encoded libraries

Jaturapitakkul¹

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Correction to “Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors”

Cited by 1 publication

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Efforts to expand chemistry toolbox for DNA-encoded libraries

Efforts to expand chemistry toolbox for DNA-encoded libraries

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