Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors

Calvo, Veronica; Surguladze, David; Li, Anhu; Surman, M. D.; Malibhatla, Srikanth; Bandaru, Madhavarao; Jonnalagadda, Suresh Krishna; Adarasandi, Dr. Ravi; Velmala, Madhusudhan; Singireddi, Durga Rama Prasad; Velpuri, Mahendar; Nareddy, Bhaskar Reddy; Sastry, Visweswara; Mandati, Chiranjeevi; Guguloth, Rambabu; Siddiqui, Shafi A.; Patil, Basanagoud S.; Chad, Elena; Wolfley, Jennifer R.; Gasparek, Jennifer; Feldman, Kirsten; Betzenhauser, Matthew J.; Wiens, Brent; Koszelak-Rosenblum, Mary; Zhu, Guangyu; Du, Hongyin; Rigby, Alan C.; Mulvihill, Mark J.

doi:10.1016/j.bmcl.2021.128058

Cited by 11 publications

(15 citation statements)

References 15 publications

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“…Human PERK (575-1094 Δ670-874) was purified as described previously [ 7 ]. Purified PERK protein at 11 mg/mL was mixed with 10 mM compound 11 , 24 , or 26 (in DMSO) to a final protein-inhibitor molar ratio 1:2.…”

Section: Methodsmentioning

confidence: 99%

“…Methods used to evaluate biochemical PERK activity are described and published elsewhere [ 7 ]. In brief, biochemical PERK activity is evaluated using a LanthaScreenTM (PerkinElmer) TR-FRET assay to detect phosphorylation of a GFP-tagged eIF2a substrate (ThermoFisher).…”

Section: Methodsmentioning

confidence: 99%

“…In cancer, acute activation of UPR enables tumors to overcome deleterious ER stress induced by rapid cell proliferation, nutrient deprivation, hypoxia, and drug treatments [ 4 , 5 , 6 ]. Pharmacological or genetic inhibition of PERK slows proliferation of tumor xenografts in mice [ 7 , 8 ], and small molecule PERK inhibitors have recently entered clinical trials for several oncology indications, including clear cell renal cell carcinoma (ccRCC) and multiple myeloma (NCT04834778; NCT05027594).…”

Section: Introductionmentioning

confidence: 99%

“…Previously described medicinal chemistry efforts around PERK inhibitors have made use of a variety of core hinge-binding regions, including aminopyridines, pyrrolopyrimidines, quinazolines, and quinolines [ 7 , 8 , 17 ]. Pyrrolopyrimidine cores have been developed and approved as JAK kinase inhibitors [ 18 , 19 ], and modifications to the core scaffold can have profound effects on stability and selectivity [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Pyrrolopyrimidine cores have been developed and approved as JAK kinase inhibitors [ 18 , 19 ], and modifications to the core scaffold can have profound effects on stability and selectivity [ 17 ]. Here, we optimized the pyrrolopyrimidine core and leveraged extensive SAR information from our recently reported aminopyridine series of inhibitors to guide chemistry efforts aimed at optimizing the in vivo properties of pyrrolopyrimidine PERK inhibitors [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Stokes

Surman²,

Calvo

et al. 2022

Pharmaceutics

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The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Stokes

Surman²,

Calvo

et al. 2022

Pharmaceutics

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Phytochemical‐mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach

Al Azzani,

Nizami,

Magramane

et al. 2024

Phytotherapy Research

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Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro‐survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro‐survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress‐mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical‐induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6‐gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well‐documented mechanistic interplay between autophagy and ER stress, only a one‐way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ‐tocotrienol): ER stress‐dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies.

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Targeting apoptosis and unfolded protein response: the impact of β-hydroxybutyrate in clear cell renal cell carcinoma under glucose-deprived conditions

Roohy,

Siri,

Kohansal

et al. 2024

Mol Biol Rep

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Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors

Cited by 11 publications

References 15 publications

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Phytochemical‐mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach

Targeting apoptosis and unfolded protein response: the impact of β-hydroxybutyrate in clear cell renal cell carcinoma under glucose-deprived conditions

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