CN-122005564-A - Application of sanguinarine chloride in preparation of medicine for treating PRCC-TFE3 rearranged renal cell carcinoma

Abstract

The application discloses application of sanguinarine (Sanguinarine chloride, SGC) in preparation of medicines for treating PRCC-TFE3 rearranged renal cell carcinoma (REARRANGED RENAL CELL carcinomas, rRCC), which belongs to the technical field of biological medicines, and firstly discovers that SGC has a specific killing effect on PRCC-TFE3 rRCC cells and extremely low toxicity on normal renal cells, has a multiple antitumor mechanism, on one hand, SGC directly binds and antagonizes VEGFR2 receptors on cell membranes to block VEGFB autocrine signaling, on the other hand, SGC inhibits transcription of VEGFB through ROS/p-STAT3 axis epigenetic inhibition, in addition, SGC can inhibit lactic acid production and H3K18 lactoylation to down regulate chemokine secretion, thereby remarkably inhibiting infiltration of polymorphonuclear marrow-derived suppressor cells (PMN-MDSCs), and on the other hand, SGC shows an in vivo antitumor effect in an immune healthy mouse model, and provides a brand-new and excellent targeting and immunoregulation candidate medicine for PRCC-TFE3 rRCC lacking an effective standard therapy for clinical treatment.

Inventors

• LI DONGMEI
• Liu Xuwentai
• GAN WEIDONG

Assignees

• 南京鼓楼医院

Dates

Publication Date

20260512

Application Date

20260331

Claims (7)

1. 1. Application of sanguinarine chloride in preparing medicine for treating PRCC-TFE3 rRCC is provided.
2. 2. The use according to claim 1, wherein the medicament antagonizes VEGFR2 receptors on the surface of tumor cell membranes while inhibiting transcription of VEGFB via ROS/p-STAT3 axis.
3. 3. The use according to claim 2, wherein the medicament is capable of down-regulating the accumulation of lactic acid and lactosylation modification of histone H3 in tumor cells.
4. 4. Use according to claim 3, characterized in that the lactoylation modifications of histone H3 include H3K9 lactoylation and H3K18 lactoylation.
5. 5. A medicament or pharmaceutical composition for treating PRCC-TFE3 rRCC, wherein the medicament or pharmaceutical composition comprises an SGC.
6. 6. The medicament or pharmaceutical composition of claim 5, further comprising a PMN-MDSC depleting agent.
7. 7. The medicament or pharmaceutical composition of claim 6, wherein the PMN-MDSCs depleting agent is Ly6G neutralizing antibody.

Description

Application of sanguinarine chloride in preparation of medicine for treating PRCC-TFE3 rearranged renal cell carcinoma Technical Field The invention belongs to the technical field of biomedical targeting therapy and immunotherapy, and particularly relates to a novel application of a natural small molecular compound sanguinarine chloride (Sanguinarine chloride, SGC) in preparation of a medicament for treating PRCC-TFE3 rearranged renal cell carcinoma (PRCC-TFE 3 rRCC). Background TFE3 rearranged renal cell carcinoma (TFE 3 rRCC), also known as xp11.2 translocation/TFE 3 gene fusion related renal cell carcinoma, belongs to the family of microphthalmia related transcription factor (MiTF) tumors. TFE3 rRCC is a highly invasive type of kidney cancer, with very poor prognosis, 15% of kidney cancers in patients under 45 years old, up to 20-50% in childhood kidney cancer. More than 20 chaperone genes fused to TFE3 have been identified, with PRCC-TFE3 being the most common fusion type （Moch H, et al. The 2022 World Health Organization Classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur Urol. 2022 Nov;82(5):458-468.）, exhibiting unique biological behaviors and highly malignant characteristics. Currently, TFE3 rRCC is resistant to conventional therapies and there is no standard therapeutic regimen for this disease clinically. For advanced or metastatic patients, protocols for clear cell renal cell carcinoma (ccRCC), such as Tyrosine Kinase Inhibitors (TKIs), mTOR inhibitors or Immune Checkpoint Inhibitors (ICIs), are often used empirically. However, since fusion genes cause strong tumor heterogeneity, there is a great difference in clinical response rate of these conventional therapies, and drug resistance is extremely liable to occur. Thus, the development of specific, efficient novel therapeutic strategies for tumors with specific fusion genotypes (e.g., PRCC-TFE 3) is a current clinical pain point that is urgently addressed. The sanguinarine (Sanguinarine chloride, SGC) is a natural benzophenanthridine alkaloid extracted from plants such as Macleaya cordata and the like, has a certain anti-inflammatory activity, and a parent compound sanguinarine is a quaternary ammonium alkaloid, and SGC is in a hydrochloride form, so that the water solubility and stability are obviously improved after salification, and better application potential （Sun W, Xu Y, Liu Z, et al. Studies on pharmacokinetic properties and intestinal absorption mechanism of sanguinarine chloride: in vivo and in situ. Toxicol Mech Methods. 2025;35(1):43-52.;Pérez Palacios AF, Medina Parra JA, Córdoba Velasco DS, et al. New Strategies to Improve Drug Solubility and Its Impact on Bioavailability: A Patent Review (2015-2024). AAPS PharmSciTech. 2025;27(1):57. ;Nyamba I, Sombié CB, Yabré M, et al. Pharmaceutical approaches for enhancing solubility and oral bioavailability of poorly soluble drugs. Eur J Pharm Biopharm. 2024;204:114513）. is provided for treating PRCC-TFE3 rRCC in terms of the absorbability and the patentability of the SGC in organisms, and the molecular mechanism and application thereof in the aspects of regulating and controlling tumor lactonization modification, targeting VEGFB-VEGFR2 axis and remodelling PMN-MDSCS immune microenvironment are not reported at present. Disclosure of Invention The invention aims to provide a novel, efficient and safe medicine for treating PRCC-TFE3 rRCC, so as to solve the problem that the subtype kidney cancer lacks effective targeting and immune medicines in the prior art. In order to achieve the above object, the present invention adopts the following technical scheme: the application of sanguinarine chloride (Sanguinarine chloride, SGC) in preparing the medicine for treating PRCC-TFE3 rRCC comprises pharmaceutically acceptable carriers and dosage forms such as oral preparation, injection or targeted nano delivery system, such as lipid nano particles or polymer micelle delivery system. The mechanism of SGC action is as follows: 1) Inhibition of tumor growth by dual blocking of VEGFB-VEGFR2 signaling pathway, including direct antagonism of VEGFR2 receptor at tumor cell membrane surface, and inhibition of transcription of VEGFB by ROS/p-STAT3 axis. 2) Downregulating accumulation of lactic acid and lactoylation modifications of histone H3K9 (H3K 9 la) in tumor cells, including H3K9 lactoylation (H3K 9 la) and H3K18 lactoylation (H3K 18 la). 3) Remodelling the tumor immune microenvironment, and remarkably inhibiting infiltration of polymorphonuclear marrow-derived suppressor cells (PMN-MDSCs) into tumor tissues. 4) Secretion of the chemokines CXCL1 and/or CXCL8 is down-regulated by inhibiting lactate-driven H3K9 lactonization, thereby blocking recruitment of PMN-MDSCs. In addition, the application also provides a medicine or a medicine composition for treating PRCC-TFE3 rRCC, which comprises SGC, and can also contain pharmaceutically acceptab