Bhandari, Dipendra

Mashayekhi, Maryam

Repa, Gil

Zhou, Donghua H.

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Structure Guided Design for Improved Anticancer Compounds   Gil Repa, Dipendra Bhandari, Maryam Mashayekhi, Donghua Zhou Oklahoma State University, Stillwater, OK Introduction!!Few other public health issues can match the tax on society that cancer has placed. Contributing to this are inadequate treatments with low efficiency and large number of negative side effects. Therefore, it is necessary to develop a highly efficient low toxic cure for cancer. Cancer drug candidate SHetA2, which was developed by scientists at OSU and OUHSC, has shown promising results: it is capable of inhibiting the growth of all cancer cell lines in the National Cancer Institute without toxic side effects in animal tests[1]. Phase 0 clinical tests are currently being conducted at OUHSC for ovarian cancer prevention. The application of SHetA2 as a cure, however, is limited by its low efficiency, only killing about 80% of cancer cells and leaving the rest to continue cancerous growth. Therefore, the creation of SHetA2 analogs[2] with increased efficiency that retain low toxicity to healthy tissues would be a major advantage in combating cancer. !!Anticancer Mechanism!!!!!!Cancer Cell mortalin p53 Nucleus mortalin SHetA2 Nucleus SHetA2 1.  Mortalin sequesters the apoptotic regulator protein p53 in the cytoplasm preventing apoptosis.  2.  The SHetA2 molecule binds to mortalin and prevents formation of the complex. The displaced p53 protein is free to migrate to the nucleus and induce apoptosis[3].   Apoptotic Cell Full Length Mortalin NMR Spectroscopy!Location of the residues that exhibit the most shifted peaks during SHEtA2 binding. Molecular Modeling!SHetA2 Results!! !!Implication!!The data presented here will help guide the development of the next generation of SHetA2 derived analogs to further its potential as a cancer treatment.!!HSQC spectra and shifted peaks. Subjecting analogs to NMR study allows identification of the amino acids that are critically involved with binding. In the HSQC spectra, peaks correspond to each amino acid residue of mortalin. Peak shift observed following titration with SHetA2 indicates perturbation of that amino acid. Acknowledgements and References!!This work was generously supported by the Lew Wentz Foundation (GR), OSU President’s Fellows Faculty Research and Stephenson Cancer Research Center/Oklahoma Tobacco Settlement Endowment Trust (TSET) .  [1] Nammalwar, B., et al., SHetA2 – A Mini Review of a Promising Anticancer Drug. JSM Chemistry, 2013. 1: p. 1005. [2] Watts, F.M. Jr., et al.,  Activity of oxygen-versus sulfur-containing analogs of the Flex-Het anticancer agent SHetA2. European Journal of Medicinal Chemistry, 2018. 5: p. 720-732. [3] Benbrook, D.M., et al., SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres. Investigational New Drugs, 2014. 32: p. 412-423.   Analogs Acceptor/Donor (Lowest BE)                                                2a (-161.5 kJ/mol)  3a (-140.4 kJ/mol)  5a (-148.6 kJ/mol)  6b (-192.3 kJ/mol)    SHetA2 (-167.9 kJ/mol)  S473_CO_Lig_NH       62.46% 52.97% 8.44% 0.367% 51% S473_CO_Lig_N1H1       0.00% 82.88% 37.12% 0.00% 2.14% T474_CO_Lig_NH       0.00% 0.095% 0.00% 81.83% 30.06% T474_CO_Lig_N1H       0.00% 0.00% 0.00% 94.33% 92.76% L450_HN_Lig_O      0.00% 97.95% 65.47% 0.00% 0.00% L450_HN_Lig_O (ring A)       0.00% 0.00% 0.00% 1.31% 0.00% Comparison of SHetA2 and analogs at lowest binding energy during 50 ns GROMACS simulation. Hydrogen bonding is indicated with dotted lines, amino acids with large contributions are shaded red. Above: Effect of increased hydrophobicity in ring A due to added geminal diethyl groups (6B).  Right: Comparison of thiourea (2A) and urea linkers (3A). Data for hydrogen bonding is summarized in the table. SHetA2 Analog 5A Analog 6B •  -167.9 kJ/mol •  -192.3 kJ/mol •  -148.6 kJ/mol Analog 2A Analog 3A NO2 S NO2 O •  -161.5 kJ/mol •  -140.4 kJ/mol NO2 S NO2 S Summary of hydrogen bonding during 50 ns simulation. Percentage indicates the amount of time during simulation that hydrogen bond was formed. Note the improved performance of with increased hydrophobicity (6B), and the urea linker (3A). This data is in agreement with the biological information.  O 

Structure guided design of improved anticancer compounds

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Structure guided design of improved anticancer compounds

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