Delving into the Latest Updates on Onalespib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Onalespib (USAN/INN), Onalespib Lactate

+ [1]

Target

HSP90

Action

inhibitors

Mechanism

HSP90 inhibitors(Heat shock 90kDa proteins inhibitors)

Therapeutic Areas

NeoplasmsRespiratory DiseasesDigestive System Disorders

Active Indication

Non-Small Cell Lung CancerColorectal Cancer

Inactive Indication

Advanced breast cancerAdvanced Malignant Solid NeoplasmAdvanced Triple-Negative Breast Carcinoma+ [41]

Originator Organization

Astex Pharmaceuticals, Inc.

Active Organization

University of Uppsala

Otsuka Holdings Co., Ltd.

Inactive Organization

National Cancer Institute

Astex Pharmaceuticals, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC27H37N3O6

InChIKeyVYRWEWHOAMGLLW-WNQIDUERSA-N

CAS Registry1019889-35-0

View All Structures (2)

This phase I trial studies the side effects and best dose of olaparib and onalespib when given together in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) or ovarian, fallopian tube, primary peritoneal, or triple-negative breast cancer that has come back (recurrent). Olaparib and onalespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date19 May 2017

Sponsor / Collaborator

National Cancer Institute

NCT02503709

/ CompletedPhase 1IIT

A Phase 1 Trial of the Combination of the Heat Shock Protein-90 (HSP90) Inhibitor Onalespib (AT13387) and the Cyclin-Dependent Kinase (CDK) Inhibitor AT7519M in Patients With Advanced Solid Tumors

This phase I trial studies the side effects and best dose of onalespib and CDKI AT7519 in treating patients with solid tumors that have spread from the primary site (place where they started) to other places in the body (metastatic) or cannot be removed by surgery. Onalespib and CDKI AT7519 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date30 Sep 2016

Sponsor / Collaborator

National Cancer Institute

NCT02535338

/ CompletedPhase 1/2IIT

A Phase 1/2 Trial of Erlotinib and Onalespib Lactate in EGFR-Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date11 Apr 2016

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Onalespib

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100 Translational Medicine associated with Onalespib

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100 Patents (Medical) associated with Onalespib

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140

Literatures (Medical) associated with Onalespib

01 Dec 2025·Molecular Biology Reports

Inhibiting HSP90 changes the expression pattern of PINK1 and BNIP3 and induces oxidative stress in colon cancer cells

Article

Author: Abu-El-Rub, Ejlal ; Alzu'bi, Ayman ; Yousef, Tuqa ; Ai-Jariri, Heba F ; Alomari, Amal ; Aldamen, Ala A ; Khaswaneh, Ramada R ; Almazari, Rawan ; Almahasneh, Fatimah A ; Kasasbeh, Amani ; Al-Zoubi, Raed M

AbstractBackgroundCancer cells can modulate the expression of many proteins that are essential for supporting their uncontrolled proliferation. Heat shock protein 90 (HSP90) is ubiquitously expressed in most cell types and participates in controlling many survival pathways. Cancer cells utilize HSP90 in order to prolong their survival, thus they tend to overexpress it. Based on its importance for cancer cells, we aim to investigate the molecular mechanisms that link HSP90 inhibition in colon cancer cells with oxidative stress and mitochondrial stress—related regulators.Materials and methodsWe used RKO colon cancer cells, blocking HSP90 with the inhibitor AT13387 and HSP90 siRNA. Cell proliferation and apoptosis were measured via CCK8 ELISA and Fluorescent Apoptosis Assays. Western blotting and immunocytochemistry assessed oxidative and mitochondrial stress markers BNIP3, PINK1, GP91/NOX2, and IRE1α in treated cells.ResultsOur findings reveal that inhibiting HSP90 with AT13387 reduces RKO cell viability by suppressing proliferation and enhancing Annexin-V expression, indicative of increased apoptosis. This rise in apoptosis is associated with PINK1 downregulation and BNIP3 upregulation, markers of mitochondrial dysfunction and oxidative stress, respectively. Additionally, AT13387 treatment elevated the protein level of GP91, a marker of oxidative stress, and IRE1α, a marker of ER stress. Similarly, genetic knockdown of HSP90 in RKO cells produced comparable effects, including reduced cell survival and a decreased PINK1/BNIP3 ratio.ConclusionTargeting HSP90 in colon cancer cells disrupts their survival by decreasing PINK1 and increasing BNIP3, which activates oxidative and endoplasmic reticulum stress, ultimately triggering apoptosis.

01 Nov 2024·Biochemical and Biophysical Research Communications

Investigating NanoLuc-EGFR engineered cell lines for real-time monitoring of EGFR protein dynamics in live cells

Article

Author: Hassan, Mohammed K ; Lawrence, Theodore S ; Mehta, Ranjit K. ; Tan, Mingjia ; Markovitz, David M ; Nyati, Mukesh K. ; Nyati, Mukesh K ; Markovitz, David M. ; Hassan, Mohammed K. ; Lawrence, Theodore S. ; Zhao, Tengda ; Mehta, Ranjit K

Evaluating the steady-state protein level of the EGFR in live cells presents significant challenges compared to measuring its kinase activity. Traditional testing methods, such as immunoblotting, ELISA, and immunofluorescence assays, are generally restricted to fixed cells or cell lysates. Despite their utility, these methods are cumbersome and provide only intermittent snapshots of EGFR levels at specific time points. With emerging trends in drug development shifting toward engineering novel agents that promote protein degradation, rather than simply inhibiting kinase activity, a tool that enables real-time, quantitative detection of drug effects in live cells could catalyze advances in the field. Such an innovation would expedite the drug development process, enhancing the translation of research findings into effective, patient-centered therapies. The NanoLuc-EGFR cell line, created through CRISPR genome editing, allows for the continuous tracking and analysis of EGFR protein levels and their degradation within live cells. This approach provides quantitative monitoring of protein dynamics in real time, offering insights that go beyond absolute protein levels to include aspects such as protein stability and degradation rate. Using this cell line model, we observed that AT13387 and H84T BanLec induce EGFR degradation in A549-HiBiT cells, with the results confirmed by immunoblotting. In contrast, Erlotinib, Osimertinib, and Cetuximab inhibit EGFR phosphorylation without altering total EGFR levels, as validated by the HiBiT luciferase assay. The NanoLuc-EGFR cell line marks a significant advancement in understanding protein regulation and serves as an instrumental platform for investigating targeted therapies that modulate protein kinases, especially those that induce protein degradation.

12 Sep 2024·Journal of Medicinal Chemistry

Allosteric Activation of Protein Phosphatase 5 with Small Molecules

Article

Author: han, Zeyu ; You, Qidong ; Gu, Jinying ; Zhao, Rongde ; Zhang, Lixiao ; Yan, Ling ; Zhang, Qiuyue ; Jiang, Cheng ; Wang, Jiayi ; Wang, Lei ; Chen, Fangsu ; Yu, Jia ; Wang, Keran ; Liu, Hua ; Yan, Yang

The activation of PP5 is essential for a variety of cellular processes, as it participates in a variety of biological pathways by dephosphorylating substrates. However, activation of PP5 by small molecules has been a challenge due to its native "self-inhibition" mechanism, which is controlled by the N-terminal TPR domain and the C-terminal αJ helix. Here, we reported the discovery of DDO-3733, a well-identified TPR-independent PP5 allosteric activator, which facilitates the dephosphorylation process of downstream substrates. Considering the negative regulatory effect of PP5 on heat shock transcription factor HSF1, pharmacologic activation of PP5 by DDO-3733 was found to reduce the HSP90 inhibitor-induced heat shock response. These results provide a chemical tool to advance the exploration of PP5 as a potential therapeutic target and highlight the value of pharmacological activation of PP5 to reduce heat shock toxicity of HSP90 inhibitors.

100 Deals associated with Onalespib

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External Link

KEGG	Wiki	ATC	Drug Bank
D10719	-	-	DB06306

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Phase 2	-	Otsuka Holdings Co., Ltd.	-
ALK-positive anaplastic large cell lymphoma	Preclinical	United States	National Cancer Institute	04 Apr 2016
Mantle cell lymphoma recurrent	Preclinical	United States	National Cancer Institute	04 Apr 2016
Recurrent Anaplastic Large Cell Lymphoma	Preclinical	United States	National Cancer Institute	04 Apr 2016
Recurrent Transformed B-Cell Non-Hodgkin Lymphoma	Preclinical	United States	National Cancer Institute	04 Apr 2016
Refractory Systemic Anaplastic Large Cell Lymphoma	Preclinical	United States	National Cancer Institute	04 Apr 2016
Metastatic castration-resistant prostate cancer	Discovery	Spain	Astex Pharmaceuticals, Inc.	01 Sep 2012
Metastatic castration-resistant prostate cancer	Discovery	United Kingdom	Astex Pharmaceuticals, Inc.	01 Sep 2012
Metastatic castration-resistant prostate cancer	Discovery	Canada	Astex Pharmaceuticals, Inc.	01 Sep 2012
Gastrointestinal Stromal Tumors	Discovery	United States	Astex Pharmaceuticals, Inc.	01 Mar 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02097225 (Cancer Therapy Evaluation Program study 9557, CTgov)	Phase 1	BRAF V600E Mutation-Positive Melanoma \| Melanoma, Cutaneous Malignant \| Metastatic Solid Tumor \| Metastatic melanoma \| Unresectable Solid Neoplasm	22	Dabrafenib+Trametinib+Onalespib (Treatment (Dabrafenib, Trametinib, Onalespib))	mpyrhvwsnt(cykktajmwk) = jqdjffqxbg jsvgfgvyux (qicivvnlcj, hzzmbpsloo - zcaozdxrae) View more	-	16 Oct 2024
	Phase 1		22	Dabrafenib+Trametinib+Onalespib (Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2)	(mhgwlbyhla) = gbsuayqnig rkpdsctder (ypevmnoyrf, ybkezgjuvg - vppcznarlj) View more	-	16 Oct 2024
NCT02097225 (Cancer Therapy Evaluation Program study 9557, Pubmed)	Phase 1	BRAF mutation Solid Tumors	22	Combination dabrafenib, trametinib, and AT13387	(ufooeibayo) = qwwzrvmvvd ymxjyobbpg (rjhexmnive, 29% - 67%) View more	-	11 Apr 2023
NCT02474173 (Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer, Pubmed \| Ther Adv Med Oncol)	Phase 1	Advanced Triple-Negative Breast Carcinoma HSP90	-	Onalespib	(fbyeugcser) = wlxrihgejp cxzyxzckmp (wjsgfqoerr ) View more	Positive	01 Jan 2023
NCT02572453 (CTgov)	Phase 2	Diffuse large B-cell lymphoma refractory \| ALK-positive anaplastic large cell lymphoma \| Refractory Systemic Anaplastic Large Cell Lymphoma \| Refractory Transformed Indolent B-Cell Non-Hodgkin Lymphoma \| Recurrent Anaplastic Large Cell Lymphoma \| Recurrent Transformed B-Cell Non-Hodgkin Lymphoma \| Mantle cell lymphoma refractory \| Mantle cell lymphoma recurrent	25	Onalespib (ALK+ ALCL)	(asqqwlizxo) = nhiqkseydm mbsmvlqizs (eziygssfcr, zovtxoxopr - rlnwnduclb) View more	-	13 Sep 2022
NCT02572453 (CTgov)	Phase 2		25	Onalespib (Relapsed MCL)	(asqqwlizxo) = nvmncvfoyq mbsmvlqizs (eziygssfcr, ouuojtyaxx - mqrxpucnui) View more	-	13 Sep 2022
NCT02535338 (NCI 9878, CTgov)	Phase 1/2	metastatic non-small cell lung cancer \| Recurrent Non-Small Cell Lung Cancer \| EGFR-mutated non-small Cell Lung Cancer	11	Pharmacological Study+Erlotinib Hydrochloride+Onalespib Lactate	(yjgkvigleb) = tnojfrntdc mryxdtsirr (zsgbtxbkdh, sgxmenjnhf - ytwjlqnole) View more	-	22 Jun 2022
NCT02535338 (NCI 9878, Pubmed \| Clin Lung Cancer) Manual	Phase 1/2	Non-Small Cell Lung Cancer	11	Erlotinib+Onalespib	(vlbuoqiicp) = zyehozmpwm zwadknibpu (dpkqeajurs, 0.9 - 5.7) View more	Negative	01 Nov 2021
NCT02503709 (Pubmed) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	28	onalespib+AT7519	(eyopghvpiz) = onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV qikdeddrmt (bfkmgeqgre ) View more	Positive	01 Dec 2020
NCT02097225 (ASCO 12020 \| ASCO 22020) Manual	Phase 1	BRAF mutation Solid Tumors BRAF V600E Mutation \| BRAF V600K Mutation	22	AT13387+dabrafenib+trametinib	(hhmgmmoafp) = Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. odprsmlcmx (otqgycagyy )	Positive	29 May 2020
NCT02474173 (ESMO2019) Manual	Phase 1	Advanced Triple-Negative Breast Carcinoma	20	paclitaxel+onalespib	(mvbknhlocb) = One DLT occurred in 1 pt in DL3 (grade 3 nausea, vomiting and abdominal pain) ndutgixiwa (gxoptvrjta ) View more	Positive	29 Sep 2019
NCT01685268 (Pubmed \| Clin Cancer Res) Manual	Phase 1/2	Prostatic Cancer	48	prednisone+prednisolone+Onalespib+Abiraterone Acetate	(kvvmjtbtyw) = qofobaobqr mioyqpvhbl (zrjcqfgtta ) View more	Negative	01 Aug 2019