Unveiling the potential of isatin-grafted phenyl-1,2,3-triazole derivatives as dual VEGFR-2/STAT-3 inhibitors: Design, synthesis and biological assessments

Article

Author: Morsy, Samar N ; Elsebaie, Heba A ; Elsayed, Zainab M ; Abdel-Aziz, Hatem A ; Abdulla, Maha-Hamadien ; Shaldam, Moataz A ; Elkaeed, Eslam B ; Tawfik, Haytham O ; Vaali Mohammed, Mansoor-Ali ; Bin Traiki, Thamer ; Eldehna, Wagdy M

The use of VEGFR-2 inhibitors as a stand-alone treatment has proven to be ineffective in clinical trials due to the robustness of cellular response loops that lead to treatment resistance when only targeting VEGFR-2. The over-activation of the signal transducer/activator of transcription 3 (STAT-3) is expected to significantly impact treatment failure and resistance to VEGFR-2 inhibitors. In this study, we propose the concept of combined inhibition of VEGFR-2 and STAT-3 to combat induced STAT-3-mediated resistance to VEGFR-2 inhibition therapy. To explore this, we synthesized new isatin-grafted phenyl-1,2,3-triazole derivatives "6a-n" and "9a-f". Screening on PANC1 and PC3 cancer cell lines revealed that compounds 6b, 6 k, 9c, and 9f exhibited sub-micromolar ranges. The most promising molecules, 6b, 6 k, 9c, and 9f, demonstrated the highest inhibition when tested as dual inhibitors on VEGFR-2 (with IC₅₀ range 53-82 nM, respectively) and STAT-3 (with IC₅₀ range 5.63-10.25 nM). In particular, triazole 9f showed the best results towards both targets. Inspired by these findings, we investigated whether 9f has the ability to trigger apoptosis in prostate cancer PC3 cells via the assessment of the expression levels of the apoptotic markers Caspase-8, Bcl-2, Bax, and Caspase-9. Treatment of the PC3 cells with compound 9f significantly inhibited the protein expression levels of VEGFR-2 and STAT-3 kinases compared to the control.

11 Apr 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy

Q1 · MEDICINE

Article

Author: Lu, Dong ; Yu, Xin ; O'Malley, Bert W ; Qin, Li ; MacKenzie, Kevin R ; Song, Xianzhou ; Yi, Ping ; Yang, Bin ; Li, Feng ; Lonard, David M ; Korp, James D ; Roy Chowdhury, Sandipan ; Chen, Jianwei ; Wang, Jin ; Bijou, Imani

Steroid receptor coactivator 3 (SRC-3) is a critical mediator of many intracellular signaling pathways that are crucial for cancer proliferation and metastasis. In this study, we performed structure-activity relationship exploration and drug-like optimization of the hit compound SI-2, guided by in vitro/in vivo metabolism studies and cytotoxicity assays. Our efforts led to the discovery of two lead compounds, SI-10 and SI-12. Both compounds exhibit potent cytotoxicity against a panel of human cancer cell lines and demonstrate acceptable pharmacokinetic properties. A biotinylated estrogen response element pull-down assay demonstrated that SI-12 could disrupt the recruitment of SRC-3 and p300 in the estrogen receptor complex. Importantly, SI-10 and SI-12 significantly inhibited tumor growth and metastasis in vivo without appreciable acute toxicity. These results demonstrate the potential of SI-10 and SI-12 as drug candidates for cancer therapy, given their potent SRC-3 inhibition and promising pharmacokinetic and toxicity profiles.

01 Aug 2023·Reproductive Sciences

Effects of STAT Inhibitors in Mouse Models of Endometriosis

Article

Author: Kadota, Yuri ; Sasada, Hikari ; Nishimura, Masato ; Aragaki, Ryousuke ; Kato, Takeshi ; Inui, Hiroaki ; Murayama, Misaki ; Nakagawa, Tomotaka ; Iwasa, Takeshi ; Shinohara, Ayaka ; Kawakita, Takako ; Kagawa, Tomohiro

The signal transducer and activator of transcription (STAT) pathway, which regulates cell proliferation and immunity, has been implicated in chronic inflammatory diseases such as rheumatoid arthritis. However, few reports have described the effects of STAT inhibitors on endometriosis, another chronic inflammatory disease. Here, we investigated the intraperitoneal microenvironment and the effects of a STAT inhibitor in a mouse model of endometriosis. In the treatment group, a STAT3 inhibitor (Stattic®, 80 mg/kg) was orally administered three times per week; control animals received orally dosed phosphate-buffered saline. Endometriosis-like lesions and peritoneal lavage fluid were collected before and 1, 2, and 3 weeks after STAT3 inhibitor administration was initiated. The lesion area was significantly increased in both groups after the first week. However, in the treatment group, the lesion areas were significantly reduced at weeks 2 and 3 compared with week 1. Transforming growth factor (TGF)-β messenger RNA (mRNA) levels in ascites cells were significantly lower at weeks 1 and 2 than at week 0. Interleukin (IL)-6 mRNA levels were significantly higher at week 1 than at week 0 but were significantly lower at weeks 2 and 3 than at week 1. Thus, STAT inhibitors appeared to reduce the extent of endometriosis in this mouse model, and may also inhibit the IL-6 signaling pathway and reduce TGF-β levels. This study suggests that STAT inhibitors warrant further exploration for use in the treatment of endometriosis.

100 Deals associated with ALD-R007

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Preclinical	US	Aluda Pharmaceuticals, Inc.Startup	30 Jan 2022
Neoplasms	Discovery	US	Aluda Pharmaceuticals, Inc.Startup	-

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