NTX-301(NTX-301) - 药物靶点：DNMT1_在研适应症：膀胱癌，急性髓性白血病，慢性粒单核细胞白血病_专利_临床

A Phase 1/2, Open-label, Dose-exploration and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of NTX-301 Monotherapy in Advanced Solid Tumours, and in Combination With Platinum-based Chemotherapy in Advanced Ovarian & Bladder Cancer, and in Combination With Temozolomide as Adjuvant (Maintenance) Therapy in High-grade Glioma (Optional Arm)

This is a Phase 1/2, open-label, dose-exploration, combination/expansion study, which will start by evaluating the safety and tolerability of NTX-301, an oral DNMT1 inhibitor, as a monotherapy in patients with advanced solid tumours, who have failed treatment with available therapies known to be active for treatment of their corresponding disease. It will then explore the safety and tolerability of NTX-301 in combination with platinum-based therapy in patients with ovarian and bladder cancer. Optionally, the safety and tolerability of NTX-301 in combination with Temozolomide (TMZ) in patients with Isocitrate Dehydrogenase 1 (IDH1) mutated high-grade glioma will also be assessed.

开始日期2021-08-25

申办/合作机构

Xennials Therapeutics, Inc.

[+1]

NCT04167917 / Recruiting临床1期IIT

A Phase 1 Study of NTX-301, an Oral DNMT1 Inhibitor, in Patients With MDS and AML

NTX-301 is a DNMT1 inhibitor. The drug is an oral drug with preclinical data that has shown preclinical anti-leukemic efficacy. This is the first clinical trial using NTX-301 in patients with myeloid malignancies.

开始日期2021-01-06

申办/合作机构

The University of Alabama at Birmingham

100 项与 NTX-301 相关的临床结果

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100 项与 NTX-301 相关的转化医学

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100 项与 NTX-301 相关的专利（医药）

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3

项与 NTX-301 相关的文献（医药）

2024-03-15·Clinical Cancer Research

Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer

Article

作者: Siu, Ellie ; Tan, Yuying ; Keathley, Russell ; Cheng, Ji-Xin ; Tanner, Edward ; Prabhu Dessai, Chinmayee Vallabh ; Wei, Jian-Jun ; Situ, Xiaolei ; Matei, Daniela ; Cardenas, Horacio ; Alhunayan, Sayedabdulrazzaq A. ; Wang, Yinu

AbstractPurpose:DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development.Experimental Design:The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy.Results:Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1–3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301–induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301–treated xenografts.Conclusions:NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.

2023-03-13·Cancers

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301.

Article

作者: Lee, Jin Soo ; Jung, DooYoung ; Ahn, Sunjoo ; Chun, Younghwa ; Lee, Ha Young ; Kim, Ji Yeon ; Choi, Gildon ; Boohaker, Rebecca J. ; Go, Areum ; Lim, Byungho ; Yoo, Dabin ; Cho, Kyung-Jin

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses. Comprehensive sensitivity profiling revealed that NTX-301 primarily exerted anticancer effects against blood cancers and exhibited improved potency against a wide range of solid cancers. Subsequent assays showed that the superior efficacy of NTX-301 depended on its strong effects on cell cycle arrest, apoptosis, and differentiation. Due to its superior efficacy, low doses of NTX-301 achieved sufficiently substantial tumor regression in vivo. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients.

Blood Cancer Journal

The preclinical efficacy of the novel hypomethylating agent NTX-301 as a monotherapy and in combination with venetoclax in acute myeloid leukemia

Letter

作者: Go, Areum ; Choi, Daeun ; Chun, Younghwa ; Jung, Myoung Eun ; Yoo, Dabin ; Lee, Jin Soo ; Lee, Ha Young ; Cho, Kyung-Jin ; Boohaker, Rebecca J ; Lim, Byungho ; Jung, DooYoung ; Choi, Gildon

100 项与 NTX-301 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床2期	美国	Pinotbio, Inc.	-
慢性粒单核细胞白血病	临床2期	美国	Pinotbio, Inc.	-
骨髓增生异常综合征	临床2期	美国	Pinotbio, Inc.	-
实体瘤	临床2期	美国	Pinotbio, Inc.	-
高级别胶质瘤	临床1期	澳大利亚	Pinotbio, Inc.	2021-08-25
高级别胶质瘤	临床1期	澳大利亚	Xennials Therapeutics, Inc.	2021-08-25
尿路上皮癌	临床1期	澳大利亚	Xennials Therapeutics, Inc.	2021-05-01
尿路上皮癌	临床1期	澳大利亚	Xennials Therapeutics, Inc.	2021-05-01
胶质瘤	临床前	澳大利亚	Xennials Therapeutics, Inc.	2021-05-01
卵巢癌	临床前	澳大利亚	Xennials Therapeutics, Inc.	2021-05-01