Delving into the Latest Updates on HTMC-0435 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PARP1 x PARP2

Action

inhibitors

Mechanism

PARP1 inhibitors(Poly (ADP-Ribose) polymerase 1 inhibitors), PARP2 inhibitors(Poly (ADP-Ribose) Polymerase 2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [3]

Active Indication

Advanced biliary tract cancerAdvanced Malignant Solid NeoplasmNeuroendocrine tumor of pancreas+ [5]

Inactive Indication

Ovarian Cancer

Originator Organization

Shanghai Huilun Life Science & Technology Co. Ltd.

Active Organization

Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.

Shanghai Huilun Life Science & Technology Co. Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (United States)

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主要目的：初步评价HTMC0435片治疗晚期胆道癌患者的有效性，在 II期临床推荐给药剂量（RP2D）下探索初步疗效。次要目的：评价HTMC0435片治疗晚期胆道癌患者的安全性；考察HTMC0435片在晚期胆道癌患者中的药代动力学（PK）特征。

[Translation]

Primary objective: To preliminarily evaluate the effectiveness of HTMC0435 tablets in the treatment of patients with advanced biliary tract cancer and explore the preliminary efficacy at the Phase II clinical recommended dose (RP2D). Secondary objective: To evaluate the safety of HTMC0435 tablets in the treatment of patients with advanced biliary tract cancer; to investigate the pharmacokinetic (PK) characteristics of HTMC0435 tablets in patients with advanced biliary tract cancer.

Start Date17 Oct 2023

Sponsor / Collaborator

Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.

[+1]

CTR20230616

/ RecruitingPhase 2

一项评价口服HTMC0435片在晚期胰腺癌患者中的有效性和安全性的II期临床试验

[Translation] A Phase II Clinical Trial to Evaluate the Efficacy and Safety of Oral HTMC0435 Tablets in Patients with Advanced Pancreatic Cancer

主要目的：初步评价HTMC0435片治疗晚期胰腺癌患者的有效性，在RP2D剂量下探索初步疗效。次要目的：评价HTMC0435片治疗晚期胰腺癌患者的安全性；考察HTMC0435片在晚期胰腺癌患者中的药代动力学（PK）特征。

[Translation]

Primary purpose: To preliminarily evaluate the effectiveness of HTMC0435 tablets in the treatment of patients with advanced pancreatic cancer and explore the preliminary efficacy at the RP2D dose. Secondary purpose: To evaluate the safety of HTMC0435 tablets in the treatment of patients with advanced pancreatic cancer; to investigate the pharmacokinetic (PK) characteristics of HTMC0435 tablets in patients with advanced pancreatic cancer.

Start Date09 Oct 2023

Sponsor / Collaborator

Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.

[+1]

CTR20233204

/ RecruitingPhase 2

一项评价口服HTMC0435片联合替莫唑胺在晚期实体瘤患者中的有效性和安全性的II期临床试验

[Translation] A phase II clinical trial evaluating the efficacy and safety of oral HTMC0435 tablets combined with temozolomide in patients with advanced solid tumors

主要目的：评价HTMC0435片联合替莫唑胺在晚期实体瘤患者中的有效性。次要目的：评价HTMC0435片联合替莫唑胺治疗晚期实体瘤患者的安全性。

[Translation]

Primary objective: To evaluate the efficacy of HTMC0435 tablets combined with temozolomide in patients with advanced solid tumors. Secondary objective: To evaluate the safety of HTMC0435 tablets combined with temozolomide in the treatment of patients with advanced solid tumors.

Start Date09 Oct 2023

Sponsor / Collaborator

Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.

100 Clinical Results associated with HTMC-0435

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100 Translational Medicine associated with HTMC-0435

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100 Patents (Medical) associated with HTMC-0435

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18

Literatures (Medical) associated with HTMC-0435

01 Oct 2024·Journal of Inorganic Biochemistry

White light increases anticancer effectiveness of iridium(III) complexes toward lung cancer A549 cells

Article

Author: Niu, Yajie ; Liu, Yunjun ; Zeng, Xiandong ; Zhou, Lin ; Chen, Xiaolan ; Li, Gechang ; Chen, Jing ; Xie, Yufeng ; Yang, Yan

Anticancer activity has been extensively studies. In this article, three ligands 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (BDIP), 2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (MDIP), 2-(6-nitrobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NDIP) and their iridium(III) complexes: [Ir(ppy)₂(BDIP)](PF₆) (ppy = deprotonated 2-phenylpyridine, 3a), [Ir(ppy)₂(MDIP)](PF₆) (3b) and [Ir(ppy)₂(NDIP)](PF₆) (3c) were synthesized. The cytotoxicity of 3a, 3b, 3c against Huh7, A549, BEL-7402, HepG2, HeLa, and non-cancer NIH3T3 was tested using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results obtained from the MTT test stated clearly that these complexes demonstrated moderate or non-cytotoxicity toward Huh7, BEL-7402, HepG2 and HeLa except A549 cells. To improve the anticancer efficacy, we used white light to irradiate the mixture of cells and complexes for 30 min, the anticancer activity of the complexes was greatly enhanced. Particularly, 3a and 3b exhibited heightened capability to inhibit A549 cells proliferation with IC₅₀ (half maximal inhibitory concentration) values of 0.7 ± 0.3 μM and 1.8 ± 0.1 μM, respectively. Cellular uptake has shown that 3a and 3b can be accumulated in the cytoplasm. Wound healing and colony forming showed that 3a and 3b significantly hinder the cell migration and growth in the S phase. The complexes open mitochondrial permeability transition pore (MPTP) channel and cause the decrease of membrane potential, release of cytochrome C, activation of caspase 3, and finally lead to apoptosis. In addition, 3a and 3b cause autophagy, increase the lipid peroxidation and lead to ferroptosis. Also, 3a and 3b increase the expression of calreticulin (CRT), high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), thereby inducing immunogenic cell death.

01 Jan 2011·Drug Metabolism and DispositionQ2 · MEDICINE

A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5

Q2 · MEDICINE

Article

Author: Farah, Nadia ; Moniz, George A. ; Lai, W. George ; Wong, Y. Nancy

10-((4-Hydroxypiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one (E7016), an inhibitor of poly(ADP-ribose) polymerase, is being developed for anticancer therapy. One of the major metabolites identified in preclinical animal studies was the product of an apparent oxidation and ring opening of the 4-hydroxypiperidine. In vitro, this oxidized metabolite could not be generated by incubating E7016 with animal or human liver microsomes. Further studies revealed the formation of this unique metabolite in hepatocytes. In a NAD(P)(+)-dependent manner, this metabolite was also generated by liver S9 fractions and recombinant human flavin-containing monooxygenase (FMO) 5 that was fortified with liver cytosol fractions. In animal and human liver S9, this metabolic pathway could be inhibited by 4-methylpyrazole, bis-p-nitrophenylphosphate (BNPP), or a brief heat treatment at 50°C. Based on these results, the overall metabolic pathway was believed to involve a two-step oxidation process: dehydrogenation of the secondary alcohol in liver cytosol followed by an FMO5-mediated Baeyer-Villiger oxidation in liver microsomes. The two oxidation steps were coupled via regeneration of NAD(P)(+) and NAD(P)H. To further confirm this mechanism, the proposed ketone intermediate was independently synthesized. In an NAD(P)H-dependent manner, the synthetic ketone intermediate was metabolized to the same ring-opened metabolite in animal and human liver microsomes. This metabolic reaction was also inhibited by BNPP or a brief heat treatment at 50°C. Methimazole, the substrate/inhibitor of FMO1 and FMO3, did not inhibit this reaction. The specificity of FMO5 toward catalyzing this Baeyer-Villiger oxidation was further demonstrated by incubating the synthetic ketone intermediate in recombinant enzymes.

01 Dec 2010·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Minocycline Protects Cardiac Myocytes Against Simulated Ischemia–Reperfusion Injury by Inhibiting Poly(ADP-ribose) Polymerase-1

Q4 · MEDICINE

Article

Author: Kim, Sun Hee ; Karliner, Joel S. ; Alano, Conrad C. ; Honbo, Norman ; Tao, Rong

There is an increase in reactive oxygen and nitrogen species in cardiomyocytes during myocardial ischemia/reperfusion injury. This leads to oxidative DNA damage and activation of nuclear repair enzymes such as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 activation promotes DNA repair under normal conditions. However, excessive activation of PARP-1 leads to cell death. We report that PARP-1 enzymatic activity is directly inhibited by minocycline, and we propose that one mechanism of minocycline cardioprotection is the result of PARP-1 inhibition. Using cultured adult rat cardiac myocytes, we evaluated the mechanism of minocycline protection in which PARP-1 activation was induced by simulated ischemia/reperfusion injury using oxygen–glucose deprivation.We found an increase in reactive oxygen species production, PARP-1 activation, and PARP-1-mediated cell death after simulated ischemia/reperfusion. Cell death was significantly reduced by the PARP inhibitors 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (10 μM) and PJ-34 (500 nM) or by minocycline (500 nM). Cellular NAD(+) depletion and poly(ADP-ribose) formation, which are biochemical markers of PARP-1 activation, were also blocked by minocycline. Finally, simulated ischemia/reperfusion led to induction of the mitochondrial permeability transition, which was prevented by minocycline. Therefore, we propose that the protective effect of minocycline on cardiac myocyte survival is the result of inhibition of PARP-1 activity.

100 Deals associated with HTMC-0435

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ovarian Cancer	Phase 3	China	Shanghai Huilun Life Science & Technology Co. Ltd.	10 Dec 2019
Prostatic Cancer	Phase 3	China	Shanghai Huilun Life Science & Technology Co. Ltd.	10 Dec 2019
Advanced biliary tract cancer	Phase 2	China	Shanghai Huilun Life Science & Technology Co. Ltd.	17 Oct 2023
Advanced Malignant Solid Neoplasm	Phase 2	China	Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.	09 Oct 2023
Neuroendocrine tumor of pancreas	Phase 2	China	Shanghai Huilun Life Science & Technology Co. Ltd.	09 Oct 2023
Extensive stage Small Cell Lung Cancer	Phase 2	China	Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.	03 Feb 2023
Advanced Lung Small Cell Carcinoma	Phase 2	China	Shanghai Huilun Life Science & Technology Co. Ltd.	11 Oct 2022
Castration-Resistant Prostatic Cancer	IND Approval	China	Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.	28 Jul 2023
Advanced Pancreatic Adenocarcinoma	IND Approval	China	Shanghai Huilun Life Science & Technology Co. Ltd.	07 Mar 2022
Small Cell Lung Cancer	Preclinical	United States	Shanghai Yidian Pharmaceutical Technology Development Co., Ltd.	09 Jan 2024