Preclinical evaluation of LX-086, a small molecule as a selective inhibitor of PI3K.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15662-e15662
Author(s):  
Jiaqiang Dong ◽  
Tie-Lin Wang ◽  
Jingjie Huang ◽  
Ji Zhou ◽  
Ye Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Small Molecule ◽  
Inhibitory Activity ◽  
Pik3ca Mutation ◽  
Selective Inhibitor ◽  
Solid Cancer ◽  
Kinase Inhibitory Activity

e15662 Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. PI3Kα is ubiquitously expressed, and associates with angiogenesis and glucose homeostasis. Gain of function mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common somatic alterations in solid tumors. The purpose of this study is to investigate the in vitro/ in vivo antitumor activity, and safety of LX-086, a small molecule of PI3Kα selective inhibitor, in preclinical models of solid cancer with PIK3CA mutation or amplification. Methods: Kinase inhibitory activity and selectivity of LX-086 were determined with PI3K kinase assays. Cellular pAktS473 inhibitory activity and selectivity were evaluated in BT-474, MDA-MB-468, RAW264.7 and Jeko-1 cell lines (cell lines PI3Kα/β/γ/δ are specifically highly expressed respectively). The antitumor activity of LX-086 was evaluated in vivo in PIK3CA amplified or mutant breast cancer BT-474, T47D and ovarian cancer SK-OV-3 cell-derived mouse xenograft (CDX) models. Results: LX-086 displayed potent kinase inhibitory activity for WT PI3Kα, PI3KαE545K, PI3KαH1047R with IC50 1.80 nM/1.13 nM/0.69 nM, respectively. LX-086 inhibited cell pAktS473 in BT-474 cells with IC50 35.4 nM. The selectivity of LX-086 in PI3Kα over PI3Kβ/δ/γ is similar with that of alpelisib, which had been approved by FDA in 2019. LX-086 showed antitumor efficacy in HER2+/HR+, PIK3CA amplified breast cancer BT-474 CDX model (TGI = 106% @40 mpk, QD), as well as in the HER2-/HR+, PIK3CA H1047R breast cancer T47D CDX model ( TGI = 84.7%@ 40 mpk, QD) and PIK3CA H1047R ovarian cancer SK-OV-3 CDX model ( TGI = 69.2%@ 40 mpk, QD). The 28-days toxicity study in dog also indicated that LX-086 had similar therapeutic index with alpelisib, with low risk of hyperglycemia. Conclusions: We have identified a novel potent and safe PI3Kα inhibitor LX-086. Preclinical studies show antitumor efficacy of LX-086 in PIK3CA mutant and amplified solid cancer models. LX-086 represents a promising clinical candidate for the treatment of solid cancers with PIK3CA mutation or amplification.

scholarly journals Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yahui Ding ◽  
Xiaoping Chen ◽  
Can Liu ◽  
Weizhi Ge ◽  
Qin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Small Molecule ◽  
Mode Of Action ◽  
Rna Silencing ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Parent Compound ◽  
Aggressive Breast Cancer

Abstract Background TNBC is the most aggressive breast cancer with higher recurrence and mortality rate than other types of breast cancer. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment. Methods Different inhibitors were used to study the cell death manner of DMOCPTL. RNA silencing was used to evaluate the functions of GPX4 in ferroptosis and apoptosis of TNBC cells and functions of EGR1 in apoptosis. Immunohistochemical assay of tissue microarray were used for investigating correlation of GPX4 and EGR1 with TNBC. Computer-aided docking and small molecule probe were used for study the binding of DMOCPTL with GPX4. Results DMOCPTL, a derivative of natural product parthenolide, exhibited about 15-fold improvement comparing to that of the parent compound PTL for TNBC cells. The cell death manner assay showed that the anti-TNBC effect of DMOCPTL mainly by inducing ferroptosis and apoptosis through ubiquitination of GPX4. The probe of DMOCPTL assay indicated that DMOCPTL induced GPX4 ubiquitination by directly binding to GPX4 protein. To the best of our knowledge, this is the first report of inducing ferroptosis through ubiquitination of GPX4. Moreover, the mechanism of GPX4 regulation of apoptosis is still obscure. Here, we firstly reveal that GPX4 regulated mitochondria-mediated apoptosis through regulation of EGR1 in TNBC cells. Compound 13, the prodrug of DMOCPTL, effectively inhibited the growth of breast tumor and prolonged the lifespan of mice in vivo, and no obvious toxicity was observed. Conclusions These findings firstly revealed novel manner to induce ferroptosis through ubiquitination of GPX4 and provided mechanism for GPX4 inducing mitochondria-mediated apoptosis through up-regulation of EGR1 in TNBC cells. Moreover, compound 13 deserves further studies as a lead compound with novel mode of action for ultimate discovery of effective anti-TNBC drug.

Targeting RECQL5 Functions, by a Small Molecule, Selectively Kills Breast Cancer in Vitro and in Vivo

2021 ◽  
Vol 64 (3) ◽  
pp. 1524-1544
Author(s):  
Saikat Chakraborty ◽  
Kartik Dutta ◽  
Pooja Gupta ◽  
Anubrata Das ◽  
Amit Das ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecule

In vivo expression and antitumor activity of p53 gene transfer with naked plasmid DNA in an ovarian cancer xenograft model in nude mice

2006 ◽  
Vol 32 (5) ◽  
pp. 449-453 ◽  
Author(s):  
Pierre Collinet ◽  
Rodolphe Vereecque ◽  
Frédéric Sabban ◽  
Denis Vinatier ◽  
Eric Leblanc ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gene Transfer ◽  
Antitumor Activity ◽  
Nude Mice ◽  
Plasmid Dna ◽  
Xenograft Model ◽  
P53 Gene ◽  
Naked Plasmid ◽  
Naked Plasmid Dna

SOMCL-863, a novel, selective and orally bioavailable small-molecule c-Met inhibitor, exhibits antitumor activity both in vitro and in vivo

2014 ◽  
Vol 351 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Lu Wang ◽  
Jing Ai ◽  
Yanyan Shen ◽  
Haotian Zhang ◽  
Xia Peng ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Small Molecule ◽  
Met Inhibitor ◽  
Orally Bioavailable

scholarly journals CSIG-29. THE DUAL PI3K/mTOR-PATHWAY INHIBITOR GDC-0084 ACHIEVES ANTITUMOR ACTIVITY IN BREAST CANCER BRAIN METASTASES IN VITRO AND IN VIVO

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi49-vi49
Author(s):  
Franziska Ippen ◽  
Christopher Alvarez-Breckenridge ◽  
Benjamin Kuter ◽  
Alexandria Fink ◽  
Ivanna Bihun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Brain Metastases ◽  
Mtor Pathway ◽  
Breast Cancer Brain Metastases

scholarly journals 11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Na Han ◽  
Yaqun Jiang ◽  
Yongkang Gai ◽  
Qingyao Liu ◽  
Lujie Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pik3ca Mutation ◽  
Phosphatidylinositol 3 Kinase ◽  
Pet Tracer ◽  
Positron Emission ◽  
Pet Scans ◽  
Mcf 7 ◽  
Phosphatidylinositol 3

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.

Preparation of RGD4C fused anti-TNFα nanobody and inhibitory activity on triple-negative breast cancer in vivo

Life Sciences ◽  
2020 ◽  
Vol 260 ◽  
pp. 118274
Author(s):  
Xuemei Ji ◽  
Tianzhen Han ◽  
Nannan Kang ◽  
Song Huang ◽  
Yu Liu
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Inhibitory Activity ◽  
Triple Negative

scholarly journals Antitumor activity of aqueous extract of Ziziphus jujube fruit in breast cancer: An in vitro and in vivo study

2015 ◽  
Vol 4 (2) ◽  
pp. 116-122 ◽  
Author(s):  
Reyhane Hoshyar ◽  
Zabihollah Mohaghegh ◽  
Nihad Torabi ◽  
Aliyeh Abolghasemi
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Aqueous Extract ◽  
In Vivo Study ◽  
Jujube Fruit ◽  
Ziziphus Jujube

MMTV/c-Neu transgenic mice as a model to study antitumor activity against breast cancer in vivo

2006 ◽  
Vol 164 ◽  
pp. S302
Author(s):  
Kyung Nan Min ◽  
Yeo Woon Kim ◽  
Ki Yoon Kim ◽  
Ji Hye Kim ◽  
Dae-Kee Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Transgenic Mice

Abstract 1525: SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo

2018 ◽  
Author(s):  
Panagiotis A. Konstantinopoulos ◽  
Graeme Hodgson ◽  
Nisha Rajagopal ◽  
Liv Johannessen ◽  
Joyce F. Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Cancer Models
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