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WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.

Zhang H, Zhang YK, Wang YJ, Kathawala RJ, Patel A, Zhu H, Sodani K, Talele TT, Ambudkar SV, Chen ZS, Fu LW - Cancer Sci. (2014)

Bottom Line: We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates.WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance.Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA.

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XP Glide predicted binding mode of WHI-P154 with homology modeled ABCG2. The docked conformation of WHI-P154 as ball and stick model is shown within the large cavity of ABCG2. Important amino acids are depicted as sticks with the atoms colored as carbon–green, hydrogen–white, nitrogen–blue, oxygen–red, whereas WHI-P154 is shown with the same color scheme as above except carbon atoms are represented in orange. Dotted black lines indicate hydrogen-bonding interactions, whereas dotted red lines indicate electrostatic interactions.
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fig05: XP Glide predicted binding mode of WHI-P154 with homology modeled ABCG2. The docked conformation of WHI-P154 as ball and stick model is shown within the large cavity of ABCG2. Important amino acids are depicted as sticks with the atoms colored as carbon–green, hydrogen–white, nitrogen–blue, oxygen–red, whereas WHI-P154 is shown with the same color scheme as above except carbon atoms are represented in orange. Dotted black lines indicate hydrogen-bonding interactions, whereas dotted red lines indicate electrostatic interactions.

Mentions: The Glide predicted docked model of WHI-P154 at Arg482 centroid-based grid of ABCG2 is shown in Figure 5. The aniline ring of WHI-P154 formed hydrophobic interactions with the side chains of Phe489, Ile573, and Pro574. The hydroxyl substituent of the aniline ring may form a hydrogen bond with the side chain of Tyr570 (HO···HO-Tyr570, 2.9 Å). This hydroxyl group was involved in hydrogen bonding interaction with the side chains of Ser486 (OH···OH-Ser486, 1.8 Å). The bromine atom present on the aniline ring entered into electrostatic interaction with the hydroxyl group of Tyr464 (Br···HO-Tyr464, 2.9 Å). The 6,7-dimethoxyquinazoline ring was stabilized into a large hydrophobic cavity formed by Phe489, Phe507, Phe511, Ala580, Leu581, Trp627 and Val631. The oxygen atom of the 7-methoxy group formed electrostatic contacts with the imidazole ring NH of His630 (CH3O···HN-His630, 4.1 Å) and side chain amino group of Asn629 (CH3O···H2N-Asn629, 4.0 Å). The N1 of the quinazoline ring was stabilized by electrostatic interaction with the side chain -NH of His630 (-N1···HN-His630, 3.7 Å).


WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.

Zhang H, Zhang YK, Wang YJ, Kathawala RJ, Patel A, Zhu H, Sodani K, Talele TT, Ambudkar SV, Chen ZS, Fu LW - Cancer Sci. (2014)

XP Glide predicted binding mode of WHI-P154 with homology modeled ABCG2. The docked conformation of WHI-P154 as ball and stick model is shown within the large cavity of ABCG2. Important amino acids are depicted as sticks with the atoms colored as carbon–green, hydrogen–white, nitrogen–blue, oxygen–red, whereas WHI-P154 is shown with the same color scheme as above except carbon atoms are represented in orange. Dotted black lines indicate hydrogen-bonding interactions, whereas dotted red lines indicate electrostatic interactions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317847&req=5

fig05: XP Glide predicted binding mode of WHI-P154 with homology modeled ABCG2. The docked conformation of WHI-P154 as ball and stick model is shown within the large cavity of ABCG2. Important amino acids are depicted as sticks with the atoms colored as carbon–green, hydrogen–white, nitrogen–blue, oxygen–red, whereas WHI-P154 is shown with the same color scheme as above except carbon atoms are represented in orange. Dotted black lines indicate hydrogen-bonding interactions, whereas dotted red lines indicate electrostatic interactions.
Mentions: The Glide predicted docked model of WHI-P154 at Arg482 centroid-based grid of ABCG2 is shown in Figure 5. The aniline ring of WHI-P154 formed hydrophobic interactions with the side chains of Phe489, Ile573, and Pro574. The hydroxyl substituent of the aniline ring may form a hydrogen bond with the side chain of Tyr570 (HO···HO-Tyr570, 2.9 Å). This hydroxyl group was involved in hydrogen bonding interaction with the side chains of Ser486 (OH···OH-Ser486, 1.8 Å). The bromine atom present on the aniline ring entered into electrostatic interaction with the hydroxyl group of Tyr464 (Br···HO-Tyr464, 2.9 Å). The 6,7-dimethoxyquinazoline ring was stabilized into a large hydrophobic cavity formed by Phe489, Phe507, Phe511, Ala580, Leu581, Trp627 and Val631. The oxygen atom of the 7-methoxy group formed electrostatic contacts with the imidazole ring NH of His630 (CH3O···HN-His630, 4.1 Å) and side chain amino group of Asn629 (CH3O···H2N-Asn629, 4.0 Å). The N1 of the quinazoline ring was stabilized by electrostatic interaction with the side chain -NH of His630 (-N1···HN-His630, 3.7 Å).

Bottom Line: We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates.WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance.Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA.

Show MeSH
Related in: MedlinePlus