Related Experiment Video

Updated: May 20, 2025

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
00:06

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

Published on: September 12, 2019

8.7K

Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma

Shuaishuai Xing1, Jiheng Jiang2, Xianglin Chu1

  • 1School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.

Journal of Medicinal Chemistry
|March 27, 2025
PubMed

Insights

A novel compound, 30, effectively targets Aldo-keto reductase 1C3 (AKR1C3) to overcome chemotherapy resistance in hepatocellular carcinoma (HCC). This strategy restores sorafenib sensitivity in resistant HCC models, offering a promising adjunct cancer therapy.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Aldo-keto reductase 1C3 (AKR1C3) is implicated in tumor progression and chemotherapy resistance, especially in sorafenib-resistant hepatocellular carcinoma (HCC).
  • Targeting AKR1C3 is a potential strategy to re-sensitize resistant HCC to chemotherapy.

Purpose of the Study:

  • To develop and optimize novel inhibitors of AKR1C3.
  • To evaluate the efficacy of a lead compound in restoring sorafenib sensitivity in HCC models.

Main Methods:

  • Cocrystal-guided drug design was employed to optimize a lead compound (S07-2005) into compound 30.
  • Compound 30's inhibitory activity, selectivity, and effects on apoptosis and ROS generation were assessed.
  • The combination therapy of compound 30 and sorafenib was evaluated in vitro and in vivo HCC models.

Main Results:

  • Compound 30 exhibited enhanced potency (IC50 = 5 ± 1 nM) and selectivity (SI > 2000) against AKR1C3 by targeting specific enzyme sites.
  • Compound 30 promoted sorafenib-induced reactive oxygen species (ROS) generation and apoptosis.
  • Combination therapy with compound 30 restored sorafenib sensitivity in HCC models, both in vitro and in vivo.

Conclusions:

  • Compound 30 is a potent and selective AKR1C3 inhibitor with favorable pharmacokinetic properties.
  • Compound 30 shows potential as an adjunct therapy to overcome AKR1C3-mediated chemoresistance in HCC.
  • This approach offers a promising strategy for treating sorafenib-resistant HCC.

More Related Videos

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

7.9K
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

14.8K

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.6K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.4K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K