A G-Quadruplex-Interactive Potent Small-Molecule Inhibitor of Telomerase Exhibiting in Vitro and in Vivo Antitumor Activity

e15642 Background: The ataxia telangiectasia and Rad3-related (ATR) kinase is a member of the phosphoinositide 3-kinase related kinase (PIKK) family. ATR plays an important role in maintaining genome integrity during DNA replication through the activation of Chk1, and regulation of the DNA damage response (DDR). Replication stress (RS) is a major source of genomic instability in cancer, and targeting the RS-response kinase ATR has emerged as a promising antitumor approach. The purpose of this study was to investigate the antitumor activity of SC0245, a small molecule inhibitor of ATR kinase, in preclinical models of ATM pathway or ARID1A deficient solid tumors. Methods: The kinase inhibiting activity of SC0245 was determined using the ATR/ATRIP(h) complex assays. The cellular anti-proliferative activity was evaluated with tumor cells which was ATM pathway or ARID1A deficient. The in vivo antitumor activity of SC0245 was evaluated in ATM pathway or ARID1A deficient cell-derived xenograft (CDX) mouse models of gastric cancer (SNU-601) and colorectal adenocarcinoma (LoVo). Results: SC0245 displayed potent kinase inhibiting activity for ATR/ATRIP complex with IC50 14 nM, and had outstanding selectivity in the 104 onco-kinase panels. SC0245 significantly inhibited cell proliferation in ATM pathway or ARID1A deficient LoVo cells with IC50 0.163 μM, SNU-601 cells with IC50 0.218 μM. SC0245 showed excellent pharmacokinetics (PK) features with oral bioavailability ( > 80%) in mouse, rat and dog. Moreover, in the SNU601 and LoVo CDX mouse models, SC0245 oral administration significantly inhibited tumor growth, with better efficacy than AZD6738. Conclusions: SC0245, a novel potent ATR kinase inhibitor, has marked antitumor efficacy in the ATM pathway or ARID1A deficient solid tumor animal models, and has outstanding PK properties. SC0245 represents a promising clinical candidate for treating solid cancers, such as gastric and colorectal cancers.

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Induction of apoptosis and antitumor effects of a small molecule inhibitor of Bcl-2 and Bcl-xl, gossypol acetate, in multiple myeloma in vitro and in vivo

Oncology Reports ◽

10.3892/or.2013.2489 ◽

2013 ◽

Vol 30 (2) ◽

pp. 731-738 ◽

Cited By ~ 14

Author(s):

JIE LIN ◽

YONGJI WU ◽

DAJUN YANG ◽

YONGQIANG ZHAO

Keyword(s):

Multiple Myeloma ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Antitumor Effects ◽

Molecule Inhibitor ◽

Induction Of Apoptosis

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An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

10.1101/2021.06.25.449993 ◽

2021 ◽

Author(s):

Joshua J Gruber ◽

Amith Rangarajan ◽

Tristan Chou ◽

Benjamin S. Geller ◽

Selene Banuelos ◽

...

Keyword(s):

Tumor Growth ◽

Small Molecule ◽

Cancer Metabolism ◽

Human Cancer ◽

Small Molecule Inhibitor ◽

Cellular Growth ◽

Acetyl Coa ◽

Molecule Inhibitor

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells lines in vitro and impaired tumor growth in vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.

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