Overcoming multidrug resistance using small molecule dynamic inhibitors by hijacking nascent and inducing turnover of mature ABCG2 for degradation in lysosomes

Review

作者: Zhang, Jian-Ting ; Liu, Jing-Yuan ; Zhang, Shaobo ; Fan, Xiuzhen ; Babula, JoAnne J ; Dong, Zizheng

ABCG2 has been associated with multidrug resistance (MDR) and protection of cancer stem cells. ABCG2 knockout had no apparent adverse effect on mice. Thus, ABCG2 is an interesting and perhaps an ideal target for drug discovery to overcome MDR and eliminate cancer stem cells. Although many ABCG2 inhibitors have been identified, few have moved into clinical testing and none has been approved. Thus, there is an unmet need for novel ABCG2 inhibitors. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTAC) and molecular-glues have been gaining traction with many in clinical trials, representing a new way targeting cytosolic proteins. However, TPD agents for membrane proteins are scarce. Recently, ABCG2 inhibitors with dynamic properties have been identified that they not only inhibit ABCG2 activity but also induce ABCG2 degradation. These dynamic inhibitors are unique and may represent a new class of TPD agents for membrane proteins and next generation inhibitors for development. Here, we investigated the mechanism of action of the dynamic inhibitor PZ-39 and its analogue PZ-39C8 and showed that they selectively bound to the extracellular loop between TM5-TM6 of ABCG2. This binding induces clathrin-dependent endocytosis of mature ABCG2 and hijacks nascent ABCG2, targeting them to lysosome via autophagy for degradation. PZ-39 also effectively induced ABCG2 loss and sensitized doxorubicin resistance in xenograft tumors. Thus, further investigation of dynamic ABCG2 inhibitors may lead to the next generation of therapeutics to overcome MDR in cancer chemotherapy and contribute to future design of TPD agents targeting membrane proteins.

2025-12-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

PyaiVS unifies AI workflows to accelerate ligand discovery and yields ABCG2 inhibitors

Article

作者: Qu, Bojian ; Wang, Lin ; Yang, Lihong ; Wang, Mukuo ; Lin, Jianping ; Jiang, Kaili

Developing optimized AI models for virtual screening requires coordinated selection of algorithms, molecular representations, and data splitting strategies, yet lacks integrated tools. We present PyaiVS, a Python package that integrates nine machine learning algorithms, five molecular representations, and three data splitting strategies. This study demonstrates that constructing efficient AI-driven virtual screening models for small molecules requires coordinated optimization of algorithm architectures (e.g., prioritizing deep learning models such as GCN, GAT, and Attentive FP), molecular representations (ECFP4/MACCS fingerprints for small datasets and molecular graph-based representations for large-scale data), and data splitting strategies (clustering-based splitting achieving 68.5 % optimal AUC-ROC performance). To demonstrate utility, we combined PyaiVS with pharmacophore modeling and docking to screen 4,188,623 compounds for ABCG2 inhibitors. Experimental validation identified four compounds (C1/C6/C7/C9) binding ABCG2 with sub-100 μM kd values (5.31-51.35 μM) that potentiate topotecan cytotoxicity. PyaiVS streamlines virtual screening by unifying critical components into an accessible platform, freely available at https://github.com/danqingmk/OpenVS_PyaiVS.

2025-11-01·PHOTOCHEMISTRY AND PHOTOBIOLOGY

A novel acquired resistance mechanism to 5‐aminolevulinic acid‐mediated photodynamic therapy with ABCG2 inhibition

Article

作者: Olsen, Jordyn ; Chandratre, Sharayu ; Chen, Bin

Abstract:

We report the occurrence of acquired tumor cell resistance to 5‐aminolevulinic acid (ALA)‐mediated photodynamic therapy (PDT) in combination with ABCG2 inhibition. ALA‐PDT in combination with either an ABCG2 tool inhibitor Ko143 or a repurposed clinically‐relevant ABCG2 inhibitor lapatinib was highly effective in eradicating the H4 human glioma cells, resulting in minimal cell survival after treatment. However, after seven rounds of repeated treatments with light dose escalation, the resultant tumor cells became resistant to the combination therapy. The resistant sublines and the parental cell line showed similar ABCG2 activities and protein levels, indicating that it was not ABCG2 that caused the resistance. They also exhibited similar responses to PpIX‐PDT and mTOR inhibitor AZD2014, suggesting that alterations in PDT sensitivity and mTOR pathway had little contribution to the development of resistance phenotype. By determining the intracellular and extracellular PpIX levels, the activities and protein levels of heme biosynthesis enzymes, we found that porphobilinogen deaminase (PBGD) activity and protein level were significantly reduced in the resistant sublines, causing resistance to PDT by substantially reducing PpIX biosynthesis. A novel acquired resistance mechanism to ALA‐PDT with ABCG2 inhibition has been uncovered.

项与 ABCG2 inhibitors(Université Claude Bernard Lyon 1) 相关的新闻（医药）

2025-10-21

·Business Wire

GondolaBio Receives U.S. FDA Orphan Drug and Fast Track Designations for PORT-77 for the Treatment of Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)

PALO ALTO, Calif.--(BUSINESS WIRE)--GondolaBio, a clinical-stage biopharmaceutical company developing novel medicines for patients living with genetic diseases, today announced that the United States (U.S.) Food and Drug Administration (FDA) has granted Orphan Drug Designation and Fast Track Designation to its affiliate, Portal Therapeutics, for PORT-77, an investigational oral, small molecule ABCG2 inhibitor, for the treatment of EPP and XLP. “For individuals living with protoporphyria, avoiding sunlight is a daily struggle that significantly affects their quality of life. The constant risk of skin and liver damage underscores the urgency of bringing disease-modifying treatments to this population as there remains a great unmet need,” said Neil Kumar, Co-founder and CEO of GondolaBio. “GondolaBio’s unique decentralized structure allows us to pursue treatments for rare diseases like EPP and XLP, and through these designations, we look forward to further collaboration with FDA as we advance this program, with plans to report full Phase 2 data in the near-term.” In preclinical and Phase 1 healthy volunteer studies, PORT-77 has demonstrated the ability to significantly lower plasma PPIX, which has the potential to address both the phototoxic and hepatobiliary impacts of EPP and XLP. PPIX reduction occurred within hours after dosing via rapid ABCG2 inhibition with no serious adverse events and no safety or tolerability signals identified to date. The FDA grants Orphan Drug Designation to support the development and evaluation of new treatments for rare diseases, defined as conditions affecting fewer than 200,000 people in the U.S. Benefits include potential eligibility for expedited review pathways, tax credits for qualified clinical trials, fee waivers, and seven years of market exclusivity after approval. Fast Track is a process designed by the FDA to facilitate the development and expedite the review of investigational drugs intended to treat serious conditions and for which nonclinical or clinical data demonstrate the potential to address unmet medical need. Therapeutic candidates with Fast Track Designation may also be eligible for priority review and accelerated approval if supported by clinical data. About Erythropoietic Protoporphyria and X-linked Protoporphyria EPP and XLP, which affects greater than 25,000 people in the U.S. and EU, are genetic photodermatoses that result in the accumulation of protoporphyrin IX (PPIX). Affected patients experience cutaneous damage and excruciating pain when exposed to sunlight. Approximately 20-30% of patients with EPP/XLP will experience some type of liver damage with up to 5% of patients progressing to acute liver failure and requiring a liver transplant. There are no approved disease-modifying treatments available. About PORT-77 PORT-77 is an oral, small molecule ABCG2 inhibitor currently in Phase 2 development for EPP and XLP. PORT-77 is designed to limit efflux of PPIX from the red blood cell to the plasma and from hepatocytes to the biliary tract, representing a potentially disease-modifying, best-in-class treatment that addresses the root cause of EPP and XLP. The ongoing clinical program is designed to determine if PORT-77 can effectively reduce plasma PPIX to improve sunlight sensitivity and reduce liver damage. About GondolaBio GondolaBio is a clinical-stage biopharmaceutical company focused on developing novel medicines for patients living with genetic diseases. A sister company of BridgeBio Pharma, GondolaBio aims to leverage cutting-edge biological research to create breakthrough medicines addressing high unmet needs across multiple therapeutic areas, modalities, and stages ranging from early discovery to clinical development. Its team of experienced drug discoverers, developers and innovators are committed to translating advances in genetic science into medicines that can help patients as quickly as possible.

孤儿药临床2期快速通道临床1期加速审批

100 项与 ABCG2 inhibitors(Université Claude Bernard Lyon 1) 相关的药物交易

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