Hot-spot guided design of macrocyclic inhibitors of the LSD1-CoREST1 interaction

Hart, Peter ’t; Openy, Joseph; Krzyzanowski, Adrian; Adihou, Hélène; Waldmann, Herbert

doi:10.1016/j.tet.2019.130685

Cited by 4 publications

(5 citation statements)

References 37 publications

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“…The cyclic peptide 34 was a PPI inhibitor of LSD1-CoREST1 with an IC 50 value of 21.9 ± 7.6 μM (Figure 8). 90 ■ CONCLUSION AND FUTURE PERSPECTIVES…”

Section: ■ Miscellaneous Peptidesmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

Baby,

Shinde,

Kulkarni

et al. 2023

ACS Chem. Biol.

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Aberrant expression of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been associated with the incidence of many diseases, particularly cancer, and it has evolved as a promising epigenetic target over the years for treatment. The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat). There is parallel mining for peptide-based LSD1 inhibitors, which exploits the opportunities in the LSD1 substrate binding pocket. This Review highlights the research progress on reversible and irreversible peptide/peptidederived LSD1 inhibitors. For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

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“…The cyclic peptide 34 was a PPI inhibitor of LSD1-CoREST1 with an IC 50 value of 21.9 ± 7.6 μM (Figure 8). 90 ■ CONCLUSION AND FUTURE PERSPECTIVES…”

Section: ■ Miscellaneous Peptidesmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

Baby,

Shinde,

Kulkarni

et al. 2023

ACS Chem. Biol.

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“…‘T Hart et al reported the hot-spot guided design and synthesis of macrocyclic peptide inhibitors of the LSD1-CoREST1 interaction in 2019 [ 92 ]. Specifically, RCM macrocyclization of 74 was performed using the Hoveyda–Grubbs II catalyst and on-resin MW irradiation to provide 75 , following final resin cleavage and deprotection by TFA.…”

Section: Microwave-assisted And/or Solid-supported Synthesis Of Macro...mentioning

confidence: 99%

“…Specifically, RCM macrocyclization of 74 was performed using the Hoveyda–Grubbs II catalyst and on-resin MW irradiation to provide 75 , following final resin cleavage and deprotection by TFA. In addition, following the removal of the Mtt-group of 76 in mildly acidic conditions, on-resin cyclization of the deprotected peptide was performed upon treatment with DIPEA to provide solid-supported 77 , followed by the conversion of thiourea to the desired guanidine and subsequent resin cleavage and side-chain deprotection to yield 78 ( Scheme 23 ) [ 92 ].…”

Section: Microwave-assisted And/or Solid-supported Synthesis Of Macro...mentioning

confidence: 99%

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Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

Sun

2022

Molecules

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Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

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“…Other groups around the world have chosen solid-phase RCM strategies for the synthesis of diverse biological interesting macrocycles, such us, inhibitors of insulin-regulated aminopeptidase, [115] antifungal peptides, [116] imidazolium-containing phosphopeptide macrocycles, [117] cyclic arodyn analogs, [118] rapamycin-inspired macrocycles, [119] LSD1 inhibitors [120] and inhibitors of the LSD1-CoREST1 interaction. [121] 5. Miscellaneous Metal-Catalyzed Solid-Phase Reactions…”

Section: Solid-phase Ring Closing Metathesismentioning

confidence: 99%

Transition Metal‐Catalyzed Reactions and Solid‐Phase Synthesis: A Convenient Blend

et al. 2022

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Transition metal‐catalyzed, C−C and C−N bond‐forming reactions have made an enormous impact in the way complex molecules are assembled. The benefits of solid‐phase chemistry soon made this type of reaction applicable to solid‐supported processes. In this review, we report the most recent applications and possibilities of this combination. Remarkably, the solid‐phase CuAAC and ring‐closing metathesis have demonstrated an important role in synthetic biology, alike more traditional Pd‐catalyzed reactions, such as Suzuki‐Miyaura, Heck, Sonogashira, which are valuable tools for accessing libraries of biologically relevant small molecules. Examples proved the validity of solid‐phase transition metal‐catalyzed reactions as a practical and fast strategy to cover the current organic chemistry demands.

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Hot-spot guided design of macrocyclic inhibitors of the LSD1-CoREST1 interaction

Cited by 4 publications

References 37 publications

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

Transition Metal‐Catalyzed Reactions and Solid‐Phase Synthesis: A Convenient Blend

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