T2AA - CAS 1380782-27-3
Category: Inhibitor
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T2AA is a proliferating cell nuclear antigen (PCNA) inhibitor. T2AA inhibits PCNA/PIP-box peptide interaction (IC50 ~1 μM), leading to the suppression of DNA replication stress by stalling DNA replication forks. T2AA inhibits the interaction of PCNA with DNA polymerase δ and arrests cell growth in S-phase.
Brife Description:
PCNA inhibitor
≥98% by HPLC
(βS)-β-Amino-4-(4-hydroxyphenoxy)-3,5-diiodobenzenpropanol; 4-[4-[(2S)-2-amino-3-hydroxypropyl]-2,6-diiodophenoxy]phenol
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1.Identification of small molecule proliferating cell nuclear antigen (PCNA) inhibitor that disrupts interactions with PIP-box proteins and inhibits DNA replication.
Punchihewa C;Inoue A;Hishiki A;Fujikawa Y;Connelly M;Evison B;Shao Y;Heath R;Kuraoka I;Rodrigues P;Hashimoto H;Kawanishi M;Sato M;Yagi T;Fujii N J Biol Chem. 2012 Apr 20;287(17):14289-300. doi: 10.1074/jbc.M112.353201. Epub 2012 Mar 1.
We have discovered that 3,3',5-triiodothyronine (T3) inhibits binding of a PIP-box sequence peptide to proliferating cell nuclear antigen (PCNA) protein by competing for the same binding site, as evidenced by the co-crystal structure of the PCNA-T3 complex at 2.1 Å resolution. Based on this observation, we have designed a novel, non-peptide small molecule PCNA inhibitor, T2 amino alcohol (T2AA), a T3 derivative that lacks thyroid hormone activity. T2AA inhibited interaction of PCNA/PIP-box peptide with an IC(50) of ~1 μm and also PCNA and full-length p21 protein, the tightest PCNA ligand protein known to date. T2AA abolished interaction of PCNA and DNA polymerase δ in cellular chromatin. De novo DNA synthesis was inhibited by T2AA, and the cells were arrested in S-phase. T2AA inhibited growth of cancer cells with induction of early apoptosis. Concurrently, Chk1 and RPA32 in the chromatin are phosphorylated, suggesting that T2AA causes DNA replication stress by stalling DNA replication forks. T2AA significantly inhibited translesion DNA synthesis on a cisplatin-cross-linked template in cells. When cells were treated with a combination of cisplatin and T2AA, a significant increase in phospho(Ser(139))histone H2AX induction and cell growth inhibition was observed.
2.A small molecule inhibitor of monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin.
Inoue A;Kikuchi S;Hishiki A;Shao Y;Heath R;Evison BJ;Actis M;Canman CE;Hashimoto H;Fujii N J Biol Chem. 2014 Mar 7;289(10):7109-20. doi: 10.1074/jbc.M113.520429. Epub 2014 Jan 28.
Small molecule inhibitors of proliferating cell nuclear antigen (PCNA)/PCNA interacting protein box (PIP-Box) interactions, including T2 amino alcohol (T2AA), inhibit translesion DNA synthesis. The crystal structure of PCNA in complex with T2AA revealed that T2AA bound to the surface adjacent to the subunit interface of the homotrimer of PCNA in addition to the PIP-box binding cavity. Because this site is close to Lys-164, which is monoubiquitinated by RAD18, we postulated that T2AA would affect monoubiquitinated PCNA interactions. Binding of monoubiquitinated PCNA and a purified pol η fragment containing the UBZ and PIP-box was inhibited by T2AA in vitro. T2AA decreased PCNA/pol η and PCNA/REV1 chromatin colocalization but did not inhibit PCNA monoubiquitination, suggesting that T2AA hinders interactions of pol η and REV1 with monoubiquitinated PCNA. Interstrand DNA cross-links (ICLs) are repaired by mechanisms using translesion DNA synthesis that is regulated by monoubiquitinated PCNA. T2AA significantly delayed reactivation of a reporter plasmid containing an ICL. Neutral comet analysis of cells receiving T2AA in addition to cisplatin revealed that T2AA significantly enhanced formation of DNA double strand breaks (DSBs) by cisplatin.
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CAS 1380782-27-3 T2AA

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