Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design

Haider, Kashif; Sharma, Anku; Yar, Mohammad Shahar; Yakkala, Prasanna Anjaneyulu; Shafi, Syed; Kamal, Ähmed

doi:10.1080/17460441.2022.2029842

Cited by 8 publications

(3 citation statements)

References 74 publications

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“…The second reason is that new predictive biomarkers are tested in different trials, including biomarkers for predicting the effectiveness of immunotherapies, such as ATM, ATR, BRCA1, BRCA2, FANCA, and POLE ( 44 , 45 ). Last, but not least, new emergent therapies will likely be a gamechanger in the BTC management, particularly KRAS inhibitors ( 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

Austrian tricentric real-life analysis of molecular profiles of metastatic biliary tract cancer patients

et al. 2023

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IntroductionMetastatic biliary tract cancer (BTC) is a rare and aggressive entity associated with poor prognosis. It represents a major challenge for adequate treatment strategies. In recent years, BTC has become a model for precision medicine in gastrointestinal oncology. Therefore, the analysis of the individual molecular profile in BTC patients may lead to targeted therapies for the benefit of patients.MethodsIn this Austrian, tricentric, real-world, retrospective analysis, we investigated patients diagnosed with metastatic BTC who underwent molecular profiling between 2013 and 2022.ResultsIn total, 92 patients were identified in this tricentric analysis and 205 molecular aberrations, including 198 mutations affecting 89 different genes in 61 patients were found. The predominant mutations were in KRAS (n=17; 22.4%), TP53 (n=17; 22.4%), PIK3CA (n=7; 9.2%), FGFR2 (n=7; 9.2%), DNMT3A (n=7; 9.2%), IDH1 (n=7; 9.2%), IDH2 (n=6; 7.9%), CDKN2A (n=6; 7.9%), BAP1 (n=4; 5.3%), NF1 (n=4; 5.3%), and NF2 (n=4; 5.3%). Three patients had HER2 amplification. MSI-H status and FGFR2 fusion genes were each observed in two different patients. One patient had a BRAF V600E mutation. Eventually, 10 patients received targeted therapy, of whom one-half derived clinical benefit.ConclusionsMolecular profiling of BTC patients is implementable in routine clinical practice and should be regularly employed to detect and exploit molecular vulnerabilities.

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Section: Discussionmentioning

confidence: 99%

Austrian tricentric real-life analysis of molecular profiles of metastatic biliary tract cancer patients

et al. 2023

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“…This scaffold has shown various biological properties that include such as anti‐inflammatory, anti‐proliferative and antibacterial properties [13] . Notably, these compounds exhibit diverse activities, including serving as inhibitors of the MDM2‐p53 interaction, influencing microtubules [14] and demonstrating potential as anticancer agents as depicted in Figure 1 [15] . The association of this scaffold with anti‐mitotic activities has been extensively documented [16] .…”

Section: Introductionmentioning

confidence: 99%

“…[13] Notably, these compounds exhibit diverse activities, including serving as inhibitors of the MDM2-p53 interaction, influencing microtubules [14] and demonstrating potential as anticancer agents as depicted in Figure 1. [15] The association of this scaffold with anti-mitotic activities has been extensively documented. [16] Recent studies have even proposed the potential of functionalized isatins as anti-mitotic agents.…”

Section: Introductionmentioning

confidence: 99%

Oxindoline Containing Thiazolidine‐4‐one Tethered Triazoles Act as Antimitotic Agents by Targeting Microtubule Dynamics

Shahjahan,

Naraharisetti,

Begum

et al. 2024

ChemistrySelect

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Oxindoline containing thiazolidine‐4‐ones linked triazole hybrids (24 a–l) series were synthesized by multistep synthesis and tested for their cytotoxic activity against four human cancer cell lines. Significantly higher susceptibility was observed in liver (HepG2) cancer cells. Among them conjugates 24 c and 24 e exhibited promising cytotoxicity with IC50 values of 1.64 μM, and 2.07 μM respectively when compared to the standard 5‐fluorouracil (IC50=20.8 μM) against the HepG2 cell line. Later on, these compounds changed the morphology of HepG2 cells and significantly inhibited colony formation in HepG2 in a dose‐dependent manner. The scratch assay divulged that these compounds decreased wound size and inhibited cell migration. Interestingly, they induced the cell cycle arrest at the S phase. Moreover, the DCFDA assay indicated ROS production proportionate to compound dose and AO/Eb staining revealed increased apoptotic cell count with higher doses. The tubulin polymerization assay reveals that they inhibited the microtubules and acted as antimitotic agents. In‐silico results of these conjugates also support their tubulin inhibitory properties. Interestingly, these compounds have adequate ADME‐toxicity parameters. Based on free energy calculation results, it was observed that these inhibitors influence the conformational flexibility of the target tubulin protein.

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Current advances and development strategies of targeting son of sevenless 1 (SOS1) in drug discovery

Wu,

Li,

et al. 2024

European Journal of Medicinal Chemistry

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Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design

Cited by 8 publications

References 74 publications

Austrian tricentric real-life analysis of molecular profiles of metastatic biliary tract cancer patients

Austrian tricentric real-life analysis of molecular profiles of metastatic biliary tract cancer patients

Oxindoline Containing Thiazolidine‐4‐one Tethered Triazoles Act as Antimitotic Agents by Targeting Microtubule Dynamics

Current advances and development strategies of targeting son of sevenless 1 (SOS1) in drug discovery

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