Synthesis and biological evaluation of rapamycin-derived, next generation small molecules

Guduru, Shiva Krishna Reddy; Arya, Prabhat

doi:10.1039/c7md00474e

Cited by 15 publications

(15 citation statements)

References 123 publications

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“…1) to establish the in vitro module editing system since some rapamycin derivatives 10 can be index for target derivatives (for a review of chemically synthesised derivatives of rapamycin, see ref. 18 ). If we can accurately edit the modular PKS of rapamycin, whose modules show higher homology to each other (the average homology between 14 KS domains is 91.6%.)…”

Section: Resultsmentioning

confidence: 99%

In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives

Kudo

Hashimoto

et al. 2020

Nat Commun

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One major bottleneck in natural product drug development is derivatization, which is pivotal for fine tuning lead compounds. A promising solution is modifying the biosynthetic machineries of middle molecules such as macrolides. Although intense studies have established various methodologies for protein engineering of type I modular polyketide synthase(s) (PKSs), the accurate targeting of desired regions in the PKS gene is still challenging due to the high sequence similarity between its modules. Here, we report an innovative technique that adapts in vitro Cas9 reaction and Gibson assembly to edit a target region of the type I modular PKS gene. Proof-of-concept experiments using rapamycin PKS as a template show that heterologous expression of edited biosynthetic gene clusters produced almost all the desired derivatives. Our results are consistent with the promiscuity of modular PKS and thus, our technique will provide a platform to generate rationally designed natural product derivatives for future drug development.

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Section: Resultsmentioning

confidence: 99%

In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives

Kudo

Hashimoto

et al. 2020

Nat Commun

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“…Blocking of mTORC1 will inhibit cell growth factors, nutrients, energy and oxygen status supply that are required for cell growth and proliferation. However, long-term exposure to sirolimus will inhibit mTORC2 by isolating newly synthesized mTOR molecules (Guduru and Arya, 2017).…”

Section: Research Articlementioning

confidence: 99%

Evaluation of NMU-Induced Breast Cancer Treated with Sirolimus and Sunitinib on Breast Cancer Growth

Jaffar

Sakri

Jaafar

et al. 2020

Asian Pac J Cancer Prev

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Breast cancer is a heterogeneous disease with a wide variety of clinical, pathological, and molecular characteristics, the most commonly diagnosed cancer among females and the leading cause of women cancer death (Bray et al., 2018). According to the Malaysia National Cancer Registry Report (2019), breast cancer accounted for 34.1% of all female cancer cases. Breast cancer is the leading cause of cancer death in Malaysia with total of 21,634 cases of female breast cancer was diagnosed for the period of 2012(Azizah, 2019. Hence, it is compulsory to conduct research to understand the pathogenesis of breast cancer and discover the targeted therapy for the detection and treatment of breast cancer.Estrogen hormone is important in normal mammary cells to regulate growth, differentiation and maintain homeostasis. Estrogen can acts as a mitogen that stimulates breast tissue to mitosis, and certain metabolites of estrogen also can act as carcinogens or genotoxin that directly damaging DNA, thereby causing cancer cells to form

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“…It has been found that the pipecolyl α-ketoamide of rapamycin anchored it into the proline-binding pocket, whereas the triene system was exposed for interactions with mTOR. Rapamycin displays low water-solubility and poor stability, so that rapamycin analogues (also named rapalogs) with improved biopharmaceutical properties have been developed [ 7 , 8 ] and approved by FDA (see Scheme 1 ) as the first-generation of mTOR inhibitors to fight cancer malignancies and other diseases. Apart from the weakness in poor druglike properties, the rapalogs possess a complex chemical structure [ 5 ]; therefore, the structural modifications of macrolide ring were generally limited.…”

Section: Introductionmentioning

confidence: 99%

In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules

et al. 2021

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Computer aided drug-design methods proved to be powerful tools for the identification of new therapeutic agents. We employed a structure-based workflow to identify new inhibitors targeting mTOR kinase at rapamycin binding site. By combining molecular dynamics (MD) simulation and pharmacophore modelling, a simplified structure-based pharmacophore hypothesis was built starting from the FKBP12-rapamycin-FRB ternary complex retrieved from RCSB Protein Data Bank (PDB code 1FAP). Then, the obtained model was used as filter to screen the ZINC biogenic compounds library, containing molecules derived from natural sources or natural-inspired compounds. The resulting hits were clustered according to their similarity; moreover, compounds showing the highest pharmacophore fit-score were chosen from each cluster. The selected molecules were subjected to docking studies to clarify their putative binding mode. The binding free energy of the obtained complexes was calculated by MM/GBSA method and the hits characterized by the lowest ΔGbind values were identified as potential mTOR inhibitors. Furthermore, the stability of the resulting complexes was studied by means of MD simulation which revealed that the selected compounds were able to form a stable ternary complex with FKBP12 and FRB domain, thus underlining their potential ability to inhibit mTOR with a rapamycin-like mechanism.

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Synthesis and biological evaluation of rapamycin-derived, next generation small molecules

Cited by 15 publications

References 123 publications

In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives

In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives

Evaluation of NMU-Induced Breast Cancer Treated with Sirolimus and Sunitinib on Breast Cancer Growth

In Silico Strategy for Targeting the mTOR Kinase at Rapamycin Binding Site by Small Molecules

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