Phase Ib IIT of Heat Shock Protein 90 Inhibitor TAS-116 Combined with Cyclin-dependent Kinase 4/6 Inhibitor Palbociclib in Advanced Breast Cancer Progressing on Palbociclib & Treatment-refractory Solid Tumors with Retinoblastoma Deficiency

The purpose of this study is to evaluate the safety and efficacy of TAS-116 with palbociclib in two groups of patients:
* Patients with advanced breast cancer that has become worse after taking palbociclib alone
* Patients with cancers that have an abnormality in a gene called the "retinoblastoma gene".

Start Date12 Sep 2023

Sponsor / Collaborator

Brown University

CTR20232143 / RecruitingPhase 1

一项TAS-116(pimitespib)联合伊马替尼治疗晚期胃肠道间质瘤患者的Ⅰ期研究

[Translation] A phase I study of TAS-116 (pimitespib) combined with imatinib in patients with advanced gastrointestinal stromal tumors

这是一项I期、开放性、多国、多中心研究。在中国患者剂量递增部分，将在中国患者中评估pimitespib单药治疗以及与伊马替尼联合治疗的安全性和耐受性。

[Translation]

This is a phase I, open-label, multinational, multicenter study. In the dose-escalation part of Chinese patients, the safety and tolerability of pimitespib monotherapy and combination therapy with imatinib will be evaluated in Chinese patients.

Start Date04 Sep 2023

Sponsor / Collaborator

Bushu Pharmaceuticals Ltd.

[+2]

JPRN-jRCT2031230263 / RecruitingPhase 2

Phase 2 platform study evaluating combination therapy with TAS-116 (pimitespib) in patients with malignant tumors - CHAPTER-Platform-201

Start Date25 Aug 2023

Sponsor / Collaborator

Sato Atsushi

100 Clinical Results associated with Pimitespib

100 Translational Medicine associated with Pimitespib

100 Patents (Medical) associated with Pimitespib

Literatures (Medical) associated with Pimitespib

01 Oct 2024·LIFE SCIENCES

Modulating the HSP90 control over NFκB/NLRP3/Caspase-1 axis is a new therapeutic target in the management of liver fibrosis: Insights into the role of TAS-116 (Pimitespib)

Article

Author: Hamad, Rabab S ; Khalifa, Amira Karam ; Elmorsy, Elsayed A ; Ahmed, Syed Suhail ; AlSalloom, A A ; Abdel-Reheim, Mustafa Ahmed ; Amer, Maha M ; Abdel-Hamed, Mohamed R ; Alibrahim, Alaa Oqalaa E ; Saber, Sameh ; Abozaid, Lobaina ; Taha, Hagir Hussein ; Alkhamiss, Abdullah S ; Nadwa, Eman Hassan ; Mohamed, Nahla B ; Nour-El-Din, M ; Mohamed, Enas A ; Mostafa-Hedeab, Gomaa

Aberrant activation of the NLRP3 inflammasome is recognized to induce a chronic inflammatory response in the liver, ultimately leading to hepatic fibrosis. HSP90 is suggested to regulate NLRP3 activation and its downstream signaling. This study is the first to explore the potential therapeutic role of pimitespib in mitigating liver fibrosis in rats. The results of the study revealed that pimitespib effectively suppressed hepatic inflammation and fibrogenesis by modulating HSP90's control over the NFκB/NLRP3/caspase-1 axis. In vitro experiments demonstrated that pimitespib reduced LDH levels and increased hepatocyte survival, whereas in vivo, it prolonged the survival of rats with hepatic fibrosis. Additionally, pimitespib exhibited improvements in the function and microscopic characteristics of rat livers. Pimitespib effectively inhibited NFκB, which serves as the priming signal for NLRP3 activation. Pimitespib's inhibitory effect on NLRP3, identified as an HSP90 client protein, plays a central role in the observed anti-fibrotic effect. The simultaneous inhibition of both priming and activation signals of NLRP3 by pimitespib led to a reduction in caspase-1 activity and subsequent suppression of the N-terminal fragment of gasdermin D, ultimately constraining hepatocyte pyroptotic cell death. These diverse effects were associated with a decrease in the transcription of inflammatory mediators IL-1β, IL-18, and TNF-α, as well as the fibrogenic mediators TGF-β, TIMP-1, PDGF-BB, and Col1a1. Moreover, pimitespib induced the expression of HSP70, which could further contribute to the repression of fibrosis development. In summary, our findings provide an evolutionary perspective on managing liver fibrosis, positioning pimitespib as a promising candidate for anti-inflammatory and antifibrotic therapy.

26 Sep 2024·JOURNAL OF MEDICINAL CHEMISTRY

Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects

Review

Author: Chen, Ruixian ; Wang, Chengdi ; Wang, Yuxi ; Zhang, Jifa ; Liang, Xinqi

Heat shock protein 90 (HSP90), a highly conserved member of the heat shock protein family, regulates various proteins and signaling pathways involved in cancer, making it a promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential in preclinical trials, with over 20 compounds advancing to clinical trials and showing promising results. However, the limited clinical efficacy and shared toxicity of these inhibitors restrict their further clinical use. Encouragingly, developing novel inhibitors using conventional medicinal chemistry approaches─such as selective inhibitors, dual inhibitors, protein-protein interaction inhibitors, and proteolysis-targeting chimeras─is expected to address these challenges. Notably, the selective inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize the structure, biological functions, and roles of HSP90 in cancer, analyze the clinical status of HSP90 inhibitors, and highlight the latest advancements in novel strategies, offering insights into their future development.

01 Aug 2024·ANTICANCER RESEARCH

Pimitespib, a Novel Heat Shock Protein 90 Inhibitor, Is Effective in Treating Renal Cell Carcinoma by Anti-angiogenetic Signaling

Article

Author: Makino, Tomoki ; Takahashi, Tsuyoshi ; Momose, Kota ; Teranishi, Ryugo ; Yamamoto, Kazuyoshi ; Eguchi, Hidetoshi ; Yamashita, Kotaro ; Doki, Yuichiro ; Kurokawa, Yukinori ; Tanaka, Koji ; Nakajima, Kiyokazu ; Saito, Takuro

BACKGROUND/AIM:

Most clear cell renal cell carcinomas (ccRCCs) have a dysfunctional von Hippel-Lindau tumor suppressor protein (VHL). Hypoxia-inducible factors 1 and 2 alpha (HIF1α and HIF2α) accumulate in ccRCC with dysfunctional VHL and up-regulate the vascular endothelial growth factor (VEGF) pathway and tumor angiogenesis. Recently, pimitespib (PIM), a potent ATP-competitive inhibitor of heat shock protein 90 (HSP90), was developed. PIM down-regulates the expression of HIF, a key protein in ccRCC progression, with anti-angiogenic effects. This study aimed to examine the effectiveness of PIM in ccRCC and the underlying mechanisms.

MATERIALS AND METHODS:

The efficacy and mechanism of PIM against ccRCCs was evaluated using ccRCC cell lines.

RESULTS:

PIM inhibited the VEGFR pathway by down-regulating VEGFR 2, phosphorylated VEGFR 2, and protein levels in downstream signaling pathways. The growth of ccRCC cell lines was inhibited by PIM. Furthermore, PIM inhibits HIF1α, HIF2α, and VEGF expression, suggesting that PIM may suppress angiogenesis in addition to the VEGFR pathway.

CONCLUSION:

PIM provides a novel approach for treating ccRCC and holds promise for future clinical strategies. Further in vivo and clinical research is required to elucidate the detailed relationship between the effects of PIM and ccRCC.

News (Medical) associated with Pimitespib

10 May 2023

·www.prnewswire.com

Soft Tissue Sarcoma Pipeline Space Brims With Novel Emerging Therapies with Over 125 Key Companies Working in the Domain | DelveInsight

The prevalence of soft tissue sarcoma has been rising over the past few years, which prompts the growing demand for treatment options. The increasing prevalence of soft tissue sarcoma and the growing research and development activities to develop novel therapies to treat soft tissue sarcoma to drive the market. The companies developing the potential therapies in the last stage of development include Advenchen Laboratories, Philogen, Nanobiotix, and several others. LAS VEGAS, May 10, 2023 /PRNewswire/ -- DelveInsight's ' Soft Tissue Sarcoma Pipeline Insight – 2023 ' report provides comprehensive global coverage of available, marketed, and pipeline soft tissue sarcoma therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the soft tissue sarcoma pipeline domain. Key Takeaways from the Soft Tissue Sarcoma Pipeline Report DelveInsight's soft tissue sarcoma pipeline report depicts a robust space with 125+ active players working to develop 130+ pipeline therapies for soft tissue sarcoma treatment. Key soft tissue sarcoma companies such as Advenchen Laboratories, Philogen, Gradalis, Epizyme, Chugai Pharma France, CytRx, Taiho Pharmaceuticals, KaryoPharm Therapeutics, Nanobiotix, Apexigen, Lytix Biopharma, Incyte Corporation, Iovance Biotherapeutics, Aadi Bioscience, Inc., AVEO Pharmaceuticals, Bayer, VasGene Therapeutics, Mirati Therapeutics, Novartis Pharmaceuticals, Incyte Corporation, Tracon Pharmaceuticals, Jiangsu Hengrui Medicine, Exelixis, Qbiotics, AstraZeneca, Loxo Oncology, ImmunityBio, Monopar Therapeutics, Chipscreen Biosciences, Ltd., Agenus, C4 Therapeutics, Inc., Noxopharm Limited, Moleculin Biotech, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Tracon Pharmaceuticals Inc., Guangdong Xiangxue Precision Medical Technology Co., Ltd., Cornerstone Pharmaceuticals, Takara Bio Inc., Jazz Pharmaceuticals, Lyell Immunopharma, Telix Pharmaceuticals, and others are evaluating new soft tissue sarcoma drugs to improve the treatment landscape. Promising soft tissue sarcoma pipeline therapies in various stages of development include AL-3818, Onfekafusp alfa, Vigil, Tazemetostat, Aldoxorubicin, TAS-116, Selinexor, NBTXR3, APX005M, GPX-150, LTX-315, Lenvatinib, Chiauranib, Zalifrelimab, INCB081776, LN-145-S1, ABI-009, Tivozanib, LOXO-101, sEphB4-HSA, Sitravatinib, Envafolimab, Camrelizumab, Tigilanol Tiglate, Durvalumab, Tremelimumab, CFT8634, NOX66, Liposomal Annamycin, 609A, YH001, TAEST16001, CPI-613+Hydroxychloroquine, TBI-1301, Lurbinectedin, LYL132, and others. In October 2022, LIXTE Biotechnology Holdings, Inc. announced that the Spanish Agency for Medicines and Health Products (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) had authorized a Phase 1b/randomized Phase 2 study of LB-100, the Company's lead clinical compound, plus doxorubicin versus doxorubicin alone, the global standard for initial treatment of advanced soft tissue sarcomas (ASTS). In September 2022, Immutep Limited was pleased to announce it has signed a Material Transfer Agreement ("Agreement") with the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland, to enable an investigator-initiated open-label Phase II clinical trial. The trial will evaluate Immutep's lead product candidate, efti in combination with pembrolizumab and radiotherapy in the neoadjuvant setting (prior to surgery) in up to 40 patients with select soft tissue sarcoma (STS). In September 2022, TRACON Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) has granted fast-track designation for the development of envafolimab (KN035) for patients with locally advanced, unresectable or metastatic undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) who have progressed on one or two prior lines of chemotherapy. In September 2022, Avacta Group plc announced that the US Food and Drug Administration (FDA) had granted Orphan Drug Designation (ODD) to the company's lead pre|CISION drug candidate, AVA6000, for treatment of soft tissue sarcoma.AVA6000 is a form of the generic chemotherapy doxorubicin that has been modified using the pre|CISION technology so that it is activated predominantly in the tumor with the aim of sparing healthy tissue from exposure and improving the safety, tolerability, and efficacy of the drug. In May 2022, Immix Biopharma, Inc., announced positive interim study data showing that after one cycle of treatment, ImmixBio's lead candidate IMX-110 produced 75% survival vs. 0% survival for Trabectedin (sold as YONDELIS ® by Janssen, a Johnson & Johnson Company, a U.S. FDA approved drug) in a connective tissue cancer Soft Tissue Sarcoma (STS) mice study. In this study, IMX-110 was compared against approved drugs used to treat STS. Trabectedin was dosed according to Meco et al., 2003 (trabectedin monotherapy treatment arm), and IMX-110 was administered at 2.0 mg/kg. In April 2022, Telix Pharmaceuticals Limited announced that it has entered into a license agreement with Eli Lilly and Company ("Lilly") under which Telix is granted exclusive worldwide rights to develop and commercialize radiolabelled forms of Lilly's olaratumab antibody for the diagnosis and treatment of human cancers. Telix's initial development focus will be on a rare type of cancer known as soft tissue sarcoma (STS). Request a sample and discover the recent advances in soft tissue sarcoma drug treatment @ Soft Tissue Sarcoma Pipeline Report The soft tissue sarcoma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage soft tissue sarcoma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the soft tissue sarcoma clinical trial landscape. Soft Tissue Sarcoma Overview Soft-tissue sarcomas (STS) are rare neoplasms that can develop in supporting or connective tissue, such as muscle, nerves, tendons, blood vessels, and fatty and fibrous tissues. They commonly affect the arms, legs, and trunk. They can also be found in the stomach and intestines (GIST), behind the abdomen (retroperitoneal sarcomas), and in the female reproductive system (gynecological sarcomas). Soft tissue sarcomas are classified based on the cell type involved, the nature of the malignancy, and the clinical course of the disease. The signs and soft tissue sarcoma symptoms differ greatly between patients depending on the type of soft tissue sarcoma. It is not associated with any obvious symptoms early in the course of the disease, but affected individuals may notice a slow-growing, painless mass in the affected area. Find out more about drugs for soft tissue sarcoma @ New Soft Tissue Sarcoma Drugs A snapshot of the Soft Tissue Sarcoma Pipeline Drugs mentioned in the report: Learn more about the emerging soft tissue sarcoma pipeline therapies @ Soft Tissue Sarcoma Clinical Trials Soft Tissue Sarcoma Therapeutics Assessment The soft tissue sarcoma pipeline report proffers an integral view of soft tissue sarcoma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Soft Tissue Sarcoma Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Infusion, Intra-arterial, Intradermal, Intralesional, Intratumoral, Intravenous, Oral, Parenteral, Subcutaneous Therapeutics Assessment By Molecule Type: Antibody, Antibody-drug conjugate, Cell therapy, Gene therapy, Immunotherapy, Nanoparticle, Peptide, Recombinant fusion protein, Small molecule Therapeutics Assessment By Mechanism of Action: Fibroblast growth factor receptor antagonists, Platelet-derived growth factor beta receptor antagonists, Proto oncogene protein c-kit inhibitors, Vascular endothelial growth factor receptor 3 antagonists, Vascular endothelial growth factor receptor-1 antagonists, Vascular endothelial growth factor receptor-2 antagonists, Immunostimulants, Free radical stimulants, DNA intercalators, Type II DNA topoisomerase inhibitors, Cell membrane structure modulators, Antibody-dependent cell cytotoxicity, Programmed cell death-1 receptor antagonists, T lymphocyte stimulants, Type 1 fibroblast growth factor receptor antagonists, Type 3 fibroblast growth factor receptor antagonists, Type 4 fibroblast growth factor receptor antagonists, Type-2 fibroblast growth factor receptor antagonists, Fms-like tyrosine kinase 3 inhibitors, Lymphocyte specific protein tyrosine kinase p56(lck) inhibitors; Lyn protein-tyrosine kinase inhibitors, Src-Family kinase inhibitors Key Soft Tissue Sarcoma Companies: Advenchen Laboratories, Philogen, Gradalis, Epizyme, Chugai Pharma France, CytRx, Taiho Pharmaceuticals, KaryoPharm Therapeutics, Nanobiotix, Apexigen, Lytix Biopharma, Incyte Corporation, Iovance Biotherapeutics, Aadi Bioscience, Inc., AVEO Pharmaceuticals, Bayer, VasGene Therapeutics, Mirati Therapeutics, Novartis Pharmaceuticals, Incyte Corporation, Tracon Pharmaceuticals, Jiangsu Hengrui Medicine, Exelixis, Qbiotics, AstraZeneca, Loxo Oncology, ImmunityBio, Monopar Therapeutics, Chipscreen Biosciences, Ltd., Agenus, C4 Therapeutics, Inc., Noxopharm Limited, Moleculin Biotech, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Tracon Pharmaceuticals Inc., Guangdong Xiangxue Precision Medical Technology Co., Ltd., Cornerstone Pharmaceuticals, Takara Bio Inc., Jazz Pharmaceuticals, Lyell Immunopharma, Telix Pharmaceuticals, and others. Key Soft Tissue Sarcoma Pipeline Therapies: AL-3818, Onfekafusp alfa, Vigil, Tazemetostat, Aldoxorubicin, TAS-116, Selinexor, NBTXR3, APX005M, GPX-150, LTX-315, Lenvatinib, Chiauranib, Zalifrelimab, INCB081776, LN-145-S1, ABI-009, Tivozanib, LOXO-101, sEphB4-HSA, Sitravatinib, Envafolimab, Camrelizumab, Tigilanol Tiglate, Durvalumab, Tremelimumab, CFT8634, NOX66, Liposomal Annamycin, 609A, YH001, TAEST16001, CPI-613+Hydroxychloroquine, TBI-1301, Lurbinectedin, LYL132, and others. Dive deep into rich insights for new drugs for soft tissue sarcoma treatment; visit @ Soft Tissue Sarcoma Medications Table of Contents For further information on the soft tissue sarcoma pipeline therapeutics, reach out @ Soft Tissue Sarcoma Drug Treatment Related Reports Soft Tissue Sarcoma Market Soft Tissue Sarcoma Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key soft tissue sarcoma companies, including Gem Pharmaceuticals, Lytix Biopharma, Incyte Corporation, Daiichi Sankyo, NantPharma, Iovance Biotherapeutics, Agenus, Eli Lilly and Company, Adaptimmune, Aadi, AVEO Pharmaceuticals, Amgen, among others. Soft Tissue Sarcoma Epidemiology Forecast Soft Tissue Sarcoma Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the soft tissue sarcoma epidemiology trends. Clear Cell Sarcoma Pipeline Clear Cell Sarcoma Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products and the key clear cell sarcoma companies, including Tesaro, NantPharma, Rafael Pharmaceuticals, Pfizer, among others. Ewing Sarcoma Pipeline Ewing Sarcoma Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, including clinical and non-clinical stage products, and the key Ewing sarcoma companies, including Gradalis, Inc., Shanghai Pharmaceuticals Holding Co., Ltd, Tyme, Inc, Pfizer, Hutchison Medipharma Limited, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

License out/inOrphan DrugFast TrackPhase 2

100 Deals associated with Pimitespib

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14876

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Gastrointestinal Stromal Tumors	JP	Taiho Pharmaceutical Co., Ltd.	20 Jun 2022

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 1	US	Taiho Oncology, Inc.	10 Jul 2017
Advanced Malignant Solid Neoplasm	Phase 1	IT	Taiho Oncology, Inc.	10 Jul 2017
Advanced Malignant Solid Neoplasm	Phase 1	GB	Taiho Oncology, Inc.	10 Jul 2017

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05245968 (CHAPTER-GIST-101, ESMO2023) Manual	Phase 1	Gastrointestinal Stromal Tumors Second line	12	Pimitespib + Imatinib	dhgugjepbo(bkvhbxzxfc) = umialqqdue gcwzgcdrdi (cllykeesef ) View more	Positive	21 Oct 2023
ERS2022	Not Applicable	Pulmonary Fibrosis HSP90	-	TAS-116	thociszbnk(fwmcfrqtif) = Mice treated with TAS-116, starting either 24h or 96h after HCl exposure, demonstrated downregulation of TGFβ signaling bmzsdvoijk (rxlezncufp ) View more	-	04 Sep 2022
JPRN-JapicCTI-184094 (ASCO2021)	Phase 3	Gastrointestinal Stromal Tumors	86	Pimitespib 160 mg	mhjgcbddol(zoqinntspc) = vjcxztsyeq jhvrkprsks (oiafqzmwlv, 9.2–not reached) View more	Positive	28 May 2021
JPRN-JapicCTI-184094 (ASCO2021)	Phase 3	Gastrointestinal Stromal Tumors	86	Placebo	mhjgcbddol(zoqinntspc) = pmadiqvtze jhvrkprsks (oiafqzmwlv, 5.5–not reached) View more	Positive	28 May 2021
JPRN-UMIN000032801 (EPOC1704, ASCO2020)	Phase 1	Solid tumor \| Colorectal Cancer	44	TAS-116 plus nivolumab	kaegbqwjia(wbdxwtpeeh) = smaccmkpqt ofcspxwbym (ccigipxmrb ) View more	Positive	25 May 2020
NCT02965885 (ASCO2017) Manual	Phase 1	Advanced Malignant Solid Neoplasm	52	Pimitespib	hfunwoxywn(poyelfmwji) = gastrointestinal disorders and increased creatinine vpfgntedlf (qjsfinwzdv )	Positive	05 Jun 2017
NCT02965885 (ASCO2017) Manual	Phase 1	Advanced Malignant Solid Neoplasm	52	Pimitespib (QD)		Positive	05 Jun 2017

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