Abstract
The metabolic adaptations that arise in late-stage cancers make it increasingly difficult for chemotherapeutical treatments to compete with the heightened growth rate of these mutated cells. One strategy to address this adaptation in metabolism is to target the post-translational modifier enzyme, diphtheria toxin like ADP-ribosyl transferase member 8 (ARTD8). ARTD8 has been noted to influence key enzymes within the PI3K/Akt/mTOR pathway, hyperactivate PKM2, along with assisting in the repair of double stranded DNA breaks. Both in vitro and in vivo models have shown ARTD8 as a suppressor of cancer cell growth rate. Thus, this project seeks to design a selective inhibitor against ARTD8, in aims to further understand ARTD8’s role in metastasis.
Nine novel amine and amide-based compounds were designed according to their likely interactions with the ARTD8 catalytic domain (3SMI.pdb) and docked using Autodock Vina to determine the computational binding affinity. All compounds were synthesized via reductive amination, and structurally confirmed prior to a comparative luminescence assay, evaluating their relative inhibitory activity against ARTD1 and ARTD8.
Compound 1 was the most selective towards ARTD8, reducing the enzymes activity to 36% ± 6% of the positive control, compared to 78% ± 2% for ARTD1 (Figure 1). This agreed with that predicted computationally. Compound 3 had the most significant inhibitory effect on ARTD8 in vitro, reductive the activity to only 27% ± 2% of the positive control. In conclusion, these compounds provide an informed basis for further design of ARTD8 selective inhibitors.
Nine novel amine and amide-based compounds were designed according to their likely interactions with the ARTD8 catalytic domain (3SMI.pdb) and docked using Autodock Vina to determine the computational binding affinity. All compounds were synthesized via reductive amination, and structurally confirmed prior to a comparative luminescence assay, evaluating their relative inhibitory activity against ARTD1 and ARTD8.
Compound 1 was the most selective towards ARTD8, reducing the enzymes activity to 36% ± 6% of the positive control, compared to 78% ± 2% for ARTD1 (Figure 1). This agreed with that predicted computationally. Compound 3 had the most significant inhibitory effect on ARTD8 in vitro, reductive the activity to only 27% ± 2% of the positive control. In conclusion, these compounds provide an informed basis for further design of ARTD8 selective inhibitors.
| Original language | English |
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| Pages | 35 |
| Number of pages | 1 |
| Publication status | Published - 29 Nov 2019 |
| Event | The fourth Queensland Annual Chemistry Symposium (QACS 2019) - University of Queensland, Brisbane, Australia Duration: 29 Nov 2019 → 29 Nov 2019 Conference number: 4th |
Conference
| Conference | The fourth Queensland Annual Chemistry Symposium (QACS 2019) |
|---|---|
| Abbreviated title | QACS 2019 |
| Country/Territory | Australia |
| City | Brisbane |
| Period | 29/11/19 → 29/11/19 |
| Other | This one-day program will incorporate both short communications (3-5 minutes) by students and longer presentations (10-15 minutes) by emerging researchers in three concurrent discipline-based sessions during the day, thus allowing students and other delegates to access sessions across a variety of chemistry disciplines. Plenary presentations will bring together researchers across multiple disciplines, and the symposium will be followed by a social gathering to stimulate further networking opportunities. All Queensland chemistry researchers are invited to participate at the symposium. Abstracts for oral presentations are encouraged from all disciplines including (but not limited to) Organic, Inorganic, Polymer, Physical, Analytical, Medicinal, Environmental, Chemical Education etc. |
