Outcomes of Breast and Ovarian cancer patients with HRD/BRCA gene alterations treated with PARP inhibitors at a tertiary care hospital in Eastern India. - BROCA-PI

Start Date13 Nov 2023

Sponsor / Collaborator

Institute of Medical Sciences & SUM Hospital

ChiCTR2300076588 / RecruitingPhase 2IIT

Targeted therapy of PARP inhibitors in pediatric brain tumors with ?-H2AX positive expression

Start Date18 Oct 2023

Sponsor / Collaborator-

EUCTR2022-004188-25-IT / Unknown statusPhase 2

P-ACC Trial - Phase II, single arm, multicenter, open-label study of PARP inhibitors + cisplatin in Recurrent and/or Metastatic Adenoid Cystic Carcinoma - P-ACC INDAGA

Start Date03 Mar 2023

Sponsor / Collaborator-

100 Clinical Results associated with 3-Aminobenzamide

100 Translational Medicine associated with 3-Aminobenzamide

100 Patents (Medical) associated with 3-Aminobenzamide

4,435

Literatures (Medical) associated with 3-Aminobenzamide

01 Mar 2024·Gynecologic oncology

Hypertension associated with niraparib in cancer patients: A pharmacovigilance analysis based on the FAERS database and meta-analysis of randomized controlled trials

Article

Author: Gao, Chen ; Xie, Jiyi ; Chen, Wei ; Shi, Chen ; Fu, Zhiwen ; Zhang, Cong

BACKGROUND:

Niraparib plays a crucial role in the treatment of ovarian cancer. A comprehensive understanding of the incidence and risk of hypertension associated with niraparib would be of vital importance to healthcare practitioners.

METHODS:

In this study, an observational, retrospective, pharmacovigilance study was conducted based on the FDA Adverse Event Reporting System (FAERS) database. Cases of hypertension related to niraparib were extracted for disproportionality analysis from the first quarter (Q1) of 2017 to Q1 of 2023. Moreover, a separate meta-analysis was performed using the randomized controlled trials (RCTs) on niraparib for cancer treatment published in PubMed, Embase, and Web of Science from inception to May 31st, 2023. The primary outcomes were the incidence and risk of hypertension associated with niraparib.

RESULTS:

In the FAERS, 1196 hypertension cases were found to be related to niraparib treatment. Notably, niraparib exhibited the highest level of disproportionality, as indicated by a reporting odds ratio (ROR) of 2.85 (95% CI, 2.69-3.01), suggesting a greater likelihood of causing hypertension compared to other poly-ADP-ribose polymerase (PARP) inhibitors (P < 0.01). Our safety meta-analysis included five pivotal RCTs of niraparib that reported hypertension. In comparison to placebo treatment, the meta-analysis demonstrated a significant increase in the risk of hypertension with niraparib (OR 2.84 [95% CI, 2.17-3.72], P < 0.01), with no heterogeneity observed among the studies (I² = 0%, χ² = 2.02, P = 0.73). The incidence of niraparib-induced hypertension was determined to be 16.9% (95% CI, 14.9-18.9; I² = 34%).

CONCLUSIONS:

These findings suggest that hypertension is a distinctive adverse event associated with niraparib compared to other PARP inhibitors. Niraparib significantly increases the risk of hypertension that needs early recognition and management in clinical medication.

01 Feb 2024·Cancer medicine

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

Article

Author: Matta, Bruna Palma ; de Barros Moreira, Fábio Carvalho ; Pereira Chaves, Claudia Bessa ; Dos Santos, Anna Claudia Evangelista ; Bergmann, Anke ; Scherer, Nicole de Miranda ; de Armas, Elvismary Molina ; Boroni, Mariana ; Richau, Caroline Stahnke ; Moreira, Miguel Angelo Martins

Abstract:

Background:

Approximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high‐grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss‐of‐function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression‐free survival and overall survival.

Methods:

The study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2.

Results:

A total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression‐free survival.

Conclusion:

Frequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non‐functional or non‐functional somatic variants, while eight 14.2% presented likely non‐functional or non‐functional somatic variants in BRCA1 or BRCA2.

01 Feb 2024·European journal of medicinal chemistry

Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy

Review

Author: Wan, Siyuan ; Wang, Xiaobing ; Li, Xinxin ; Luo, Zhongwen ; Kong, Lingyi ; Wang, Cheng ; Li, Shang ; Yin, Fucheng ; Zhang, Yonglei ; Chen, Yifan ; Luo, Heng

Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e, encoded KWLX-12e, with good inhibitory activity against PARP1 (IC₅₀ = 6.89 nM) and EZH2 (IC₅₀ = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC₅₀ = 2.84 μM) and BT-549 cells (IC₅₀ = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.

251

News (Medical) associated with 3-Aminobenzamide

29 May 2024

·www.prnewswire.com

AVELOS THERAPEUTICS ANNOUNCES KRW 17 BILLION SERIES B FUNDING ROUND, SURPASSING KRW 30 BILLION TOTAL RAISED

Stassets Investment Leads Round with Major Contribution, Joined by LSK Investment and Shinhan Capital Investment Provides Crucial Resources for Company's Focus on Developing Small Molecule Synthetic New Drugs in Synthetic Lethality, DNA Damage Response, and Cell Cycle Sectors First-In-Class AD1208 Preclinical Results Announced at AACR in April SEOUL, South Korea, May 29, 2024 /PRNewswire/ -- Avelos Therapeutics, a leading innovator in the development of novel anti-cancer drugs, recently completed a successful Series B funding round totaling KRW 17 billion (approximately $12.3 million USD) on April 30. Leading this effort was Stassets Investment, alongside new investors LSK Investment, Medytox Venture Investment, Shinhan Capital and Heungkuk Securities. Avelos' existing funders–SV Investment, Mirae Asset Venture Investment, Quad Investment Management and Timefolio Capital–also made financial contributions. This latest funding round brings Avelos' total raised to KRW 30 billion (approximately $21.7 million USD) between seed (KRW 2 billion), Series A (KRW 10 billion), and Series B funding. Founded on Sept. 1, 2021 by new drug development experts CEO Young Whan Park, CTO Soongyu Choi and Head of Business Development Kangsik Yun, Avelos focuses on developing small molecule synthetic drugs targeting synthetic lethality, DNA damage response and cell cycle regulation. Currently, the company is developing four new anti-cancer drug pipelines. At the forefront of Avelos' world-class innovation is AD1208, a first-in-class MASTL kinase inhibitor, preclinical candidate of the AVS1001 project designed to affect mitosis in cell cycle process and DNA damage response. This drug offers an option for cancer patients who have been unresponsive to current drugs, and can treat colon cancer, stomach cancer, breast cancer, ovarian cancer and prostate cancer. An oral medication, AD1208 demonstrates excellent efficacy in selectively inhibiting cancer cells in both laboratory and animal testing. Clinical trials are scheduled to start in the second half of the year, following preclinical toxicity study, using funding from the Series B investment. In April, Avelos disclosed preclinical research findings for AVS1001 project at the American Association for Cancer Research (AACR 2024). The company now aims to begin full-scale development. In addition to AVS1001, Avelos has three other projects in its pipeline, aimed at promising targets in the DNA damage response field. Among them, the AVS1002 project is planning to identify a development candidate by the end of this year, for treating patients with homologous recombination deficiency (HRD) in the DNA damage response. This is of significant interest to those in the field of synthetic lethality, as inhibiting this target raises expectations for effectively treating patients resistant to approved drugs in this field, especially PARP inhibitors, or those with HRD that current PARP inhibitors cannot cover. Avelos plans to select candidates later this year and conduct preclinical toxicity study in 2025. As with the development of AD1208, the Series B funding will support these advancements. With these notable achievements in research and development, Avelos plans to identify collaborative Korean research partners and facilitate global technology transfer in 2025. The company also plans to list on the KOSDAQ stock market after securing two additional clinical-stage substances. "The successful completion of the Series B investment, despite challenging conditions with decreased biotech sector investments, underscores the market's high regard for our expertise, capabilities and growth potential," said Young Whan Park, CEO of Avelos. "The global competitiveness of all treatments in development and adherence to our challenging development timeline have been critical to our success. With this investment, we aim to cultivate globally competitive new anti-cancer drugs and evolve into a leading global biotech firm specializing in world-class synthetic lethality." "Following a focus on securing our R&D pipeline, our next strategic move will include establishing a foundation for global expansion," said Soongyu Choi, Ph.D., who was promoted from CTO to co-CEO in January of this year. He also emphasizes that our scientists at Avelos design and strive for the best outcomes that increase the probability of success in novel drug development. To learn more about Avelos Therapeutics, visit avelostx.com. About Avelos Therapeutics Avelos Therapeutics is a specialized research and development (R&D) company focused on oncology drug discovery and development working with small molecule drugs for undruggable targets in the synthetic lethality, DNA damage response and cell cycle areas. Founded in 2021, the company is led by veterans in pre-clinical and clinical drug development, including CEO Young-Whan Park and Soongyu Choi. To learn more about Avelos Therapeutics, visit avelostx.com. SOURCE Avelos Therapeutics

AACRExecutive ChangePROTACs

23 May 2024

·www.fiercebiotech.com

Tango drops USP1 inhibitor over liver toxicity in patients during phase 1 trial

“While disappointing, we believe this is the right decision given the data at hand,” Tango's CEO said. Tango Therapeutics has discarded one of its cancer drugs on the dancefloor after the USP1 inhibitor was linked to reports of liver toxicity in a phase 1 trial. The biotech had been testing the safety and efficacy of the candidate, dubbed TNG348, in a phase 1/2 study in patients with BRCA1/2-mutant and other HRD+ cancers. The plan had been to add AstraZeneca’s and Merck & Co.’s PARP inhibitor Lynparza into the mix as a combo treatment, but the study never made it that far. Instead, Tango has decided to end the trial—and the TNG348 program entirely—after grade 3/4 “liver function abnormalities” were observed in patients who continued on the study for longer than eight weeks. A grade 4 event is considered life-threatening. “Patient safety is always our first priority and based on emerging data from the TNG348 dose escalation study, we have made the decision to discontinue further development of this molecule due to liver toxicity experienced by patients in the trial,” Tango’s CEO Barbara Weber, M.D., said in the May 23 release. “While disappointing, we believe this is the right decision given the data at hand,” Weber added. USP1, a deubiquitinating enzyme that regulates DNA damage response, is one of a number of emerging targets for synthetic lethality, an approach to killing cancer cells that PARP inhibitors such as Lynparza have helped put on the map over the past decade. While PARP inhibitors have validated the concept, they are unable to trigger responses in all patients and are vulnerable to resistance even when they are initially effective. Last year, Roche inked a deal to secure an exclusive global license to KSQ Therapeutics’ early-phase USP1 inhibitor. With Tango’s own USP1 ambitions up in smoke, Weber said the company will focus resources on its remaining portfolio, which is headed up by a PRMT5 program. The lead candidate, TNG908, is being assessed in a phase 1/2 in patients with MTAP-deleted tumors. Another PRMT5 drug, TNG462, is also in phase 1/2 development for various tumor types. “We remain committed to and confident in our ability to deliver a comprehensive clinical update on TNG908 and TNG462 in the second half of this year,” Weber said. Tango also has a dance partner in the form of Gilead, with a long-standing collaboration that stretches to 15 immuno-oncology targets. The biotech's shares were trading down premarket by 5.3% to $7 as of 7:12 am ET on Thursday morning.

License out/inPhase 1

23 May 2024

·www.biospace.com

Tango Stops Early Cancer Trial Over Liver Toxicity, Drops Out of Race Against Roche

Pictured: Illustration of a human body with the liver highlighted/iStock, magicmine Tango Therapeutics said Thursday it has stopped development of an early-phase synthetic lethal cancer candidate after seeing liver toxicity in recipients of the molecule. The biotech began a Phase I clinical trial of the USP1 inhibitor TNG348 in solid tumors in December 2023. Tango planned to study escalating doses of TNG348, initially as a single agent and then in combination with the PARP inhibitor Lynparza (olaparib). However, a safety signal prompted the company to stop the study before reaching the combination cohort. Investigators saw Grade 3 and 4 liver function abnormalities in patients who stayed in the study for more than eight weeks. The trial was testing TNG348 in patients with BRCA1/2-mutant and other homologous recombination deficient cancers. USP1 is a deubiquitinating enzyme that regulates DNA damage response (DDR). The enzyme’s role in DDR led researchers to study its potential in synthetic lethality, a genetic interaction when the loss of two genes leads to cell death. Preclinical studies suggest inhibitors of the enzyme work synergistically with inhibitors of PARP, the target of the pioneering synthetic lethal drug Lynparza. Early evidence that targeting USP1 may enhance the effect of drugs such as Lynparza in patients who are naïve or resistant to PARP inhibitors has attracted a small group of companies. Roche is the biggest name in the space. The Swiss drugmaker licensed the most advanced USP1 inhibitor from KSQ Therapeutics in 2023. Tango has yet to share a hypothesis for why patients had liver function abnormalities. Other developers of USP1 inhibitors appear to have avoided such problems so far. Researchers started a Phase I clinical trial of Roche’s candidate in August 2021. Enrollment stopped for several months in 2023 for an undisclosed reason but there have been no reports of safety problems. ISM3091, the USP1 inhibitor Exelixis licensed from Insilico Medicine, entered the clinic in August 2023 and the trial has continued uninterrupted. The molecules and other preclinical USP1 inhibitors share key characteristics. Tango CEO Barbara Weber discussed the similarities between the seven leading USP1 inhibitors at a Barclays event in March 2024. “The only way we and others have found to inhibit USP1 is through a single allosteric site. So, you might imagine that there's a fair amount of similarity in the molecules that have that mechanism of action,” Weber said. “I think we just have to see what the clinical data looks like. The [pharmacokinetics] ends up being an important component of that.” Nick Paul Taylor is a freelance pharmaceutical and biotech writer based in London. He can be reached on LinkedIn.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Diseases	Phase 2	AU	Inotek Pharmaceuticals Corp.	01 Oct 2005
Heart Diseases	Phase 2	IN	Inotek Pharmaceuticals Corp.	01 Oct 2005
Postoperative Complications	Phase 2	US	Inotek Pharmaceuticals Corp.	01 Oct 2005
Postoperative Complications	Phase 2	AU	Inotek Pharmaceuticals Corp.	01 Oct 2005
Postoperative Complications	Phase 2	IN	Inotek Pharmaceuticals Corp.	01 Oct 2005
Postoperative Complications	Phase 2	IL	Inotek Pharmaceuticals Corp.	01 Oct 2005
Myocardial Infarction	Phase 2	US	Inotek Pharmaceuticals Corp.	01 Jan 2004
Myocardial Infarction	Phase 2	IL	Inotek Pharmaceuticals Corp.	01 Jan 2004
Erectile Dysfunction	Phase 2	US	Inotek Pharmaceuticals Corp.	-
Glioblastoma	Phase 2	US	Inotek Pharmaceuticals Corp.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00271765 (TIMI 37, Pubmed \| J Thromb Thrombolysis)	Phase 2	ST Elevation Myocardial Infarction	40	INO-1001	vjjdvhpnpm(kmmmddxmyj) = Serial C-reactive protein levels showed a trend toward blunting of inflammation with INO-1001 lwjfpxonkq (mutdynxokh ) View more	-	01 May 2009

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