https://openworks.mdanderson.org/sumexp22/1049/thumbnail.jp

Azordegan, Hawk

Manning, Henry Charles

Pham, Cong-Dat

English

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Chemical Synthesis of Astatine Labelled ASCT2 Inhibitor Analogue  (HA01) as a Radiotherapeutic Agent for TheranosticsHawk Azordegan, Cong-Dat Pham, H. Charles ManningThe University of Texas, MD Anderson Cancer Center, Department of Cancer Systems Imaging, Houston, TXBackgroundGlutamine is an amino acid that is utilized by cancer cells as a source of energy to replicate and spread. It is the most abundant amino acid in plasma. Glutamine is able to enter the cells through the amino acid transporter ASCT2 (Neutral amino acid transporter B(0)). V-9302 is a known competitive inhibitor of ASCT2 and is capable of killing cancer cells in vitro and in vivo. However, there have been limitations to the usage of V-9302 due to toxicity in vivo and its modest potency. While there are many possibilities to enhance its efficacy such as substitution with larger π-electron rich aromatics or optimizing its pharmacophore, we chose to explore the possibility of creating a radiotherapeutic drug.Recent studies have found that alpha emitting radiotherapies have proven to have promising results in clinical settings. Astatine-211 (²¹¹At) being an alpha particle emitter of interest. This leads us to an interest in an ²¹¹At labeled ASCT2 inhibitor analogue.Figure 1.  Inhibition of ASCT2 (encoded by SLC1A5 gene) by V-9302.¹ObjectiveMethodsResultsPHASE TWO – Condensation with pharmacophorePHASE ONE – Sidechain synthesisPHASE THREE – Conjugation with radionuclide binding ligandFigure 3. Synthesis of V-9302 analogue, HA01 ligand. Synthesize a V-9302 analogue with equal or greater affinity towards ASCT2 than V-9302 that can be used for radiolabeling with ²¹¹At for radiotherapy in vivo.Figure 2.  Possibilities for changes and substitutions in V-9302.ConclusionsWe successfully synthesized HA01 in six steps. HA01’s efficacy as an ASCT2 inhibitor must now be tested through a DARTS (Drug affinity responsive target stability) assay. Assuming this assay is successful - meaning the analogue properly binds to ASCT2 - HA01 will be radiolabeled with an astatine ion to be used for radiotherapy. To prepare for this, an astatine ion will be attached to the location marked by the blue circle below and then tested in a mouse model. The analogue was synthesized using standard organic synthetic procedures (ether synthesis, reductive amination, “click”-reaction and deprotection). The intermediates were isolated by normal phase silica column (10-50% Ethyl acetate in hexane gradient) and the final products were purified by reverse phase (C-18) HPLC (10-95% acetonitrile in water gradient over 35 min).Figure 4. HA01 ligand. Blue ellipses represents astatine binding site. DCM, NaBH(AcO)3, RT, o/n DCM, NaBH(AcO)3, RT, o/n4 5 6H2NNHBocOO ONH OONHBocOOOOONNHBocOOOBrTHF, PBr3, RT, 6h DMF, NaH, RT, 19h1 2 3OOHOOOHHA01DMF:H2O, Ascorbic acid, CuSO4 x 5 H2O, TBTA, RT, o/nDioxane, RT, 1hHCl [211At] binding ligand[211At] binding ligand[211At] binding ligand6 7ONNHBocOOOONNHBocOOONNNONNH2OOHONNNReferences1) Liu, Yang, et al. “The Role of ASCT2 in Cancer: A Review.” European Journal of Pharmacology, Elsevier, 17 July 2018, https://doi.org/10.1016/j.ejphar.2018.07.007. 2) Choi, Y. K., et al. G. Targeting Glutamine Metabolism for CancerTreatment. Biomolecules & therapeutics, 26(1), 19–28 (2018).3) Jin, L., et al. Glutaminolysis as a target for cancer therapy. Oncogene 35, 3619–3625 (2016).4) Suzuki, Hiroyuki , et al. “Neopentyl Glycol as a Scaffold to Provide Radiohalogenated Theranostic Pairs of High In Vivo Stability” Journal of Medicinal Chemistry 2021 64 (21), 15846-15857.5) Zalutsky R. Michael and Vaidyanathan Ganesan, Astatine-211-Labeled Radiotherapeutics An Emerging Approach to Targeted Alpha-Particle Radiotherapy, Current Pharmaceutical Design 2000; 6(14) . https://dx.doi.org/10.2174/1381612003399275AcknowledgmentsThe authors would like to thank the CPRIT-CURE summer experience and the Manning Lab for supporting this study and creating the opportunity for an undergraduate student to get involved in the field of theranostics. 

Chemical Synthesis of Astatine Labelled ASCT2 Inhibitor Analogue  (HA01) as a Radiotherapeutic Agent for Theranostics

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1049&context=sumexp22

Chemical Synthesis of Astatine Labelled ASCT2 Inhibitor Analogue (HA01) as a Radiotherapeutic Agent for Theranostics

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