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

Mechanism

HSP90 inhibitors(Heat shock 90kDa proteins inhibitors)

Therapeutic Areas

NeoplasmsRespiratory DiseasesMouth and Tooth Diseases+ [3]

Active Indication

Non-Small Cell Lung CancerLocally Advanced Head and Neck Squamous Cell CarcinomaSquamous cell carcinoma of the hypopharynx+ [4]

Inactive Indication

Advanced breast cancerAdvanced Malignant Solid NeoplasmAdvanced Triple-Negative Breast Carcinoma+ [33]

Originator Organization

Astex Pharmaceuticals, Inc.

Active Organization

National Cancer Institute

University of UppsalaOtsuka Holdings Co., Ltd.

Inactive Organization

Astex Pharmaceuticals, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

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 / Active, not recruitingPhase 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 Date08 Apr 2016

Sponsor / Collaborator

National Cancer Institute

NCT02572453 / TerminatedPhase 2IIT

Phase 2 Trial of the Heat Shock Protein-90 (Hsp90) Inhibitor AT13387 (Onalespib) in Patients With Relapsed/Refractory ALK+ ALCL, Mantle Cell Lymphoma, and BCL6+ DLBCL

This phase II trial studies how well onalespib works in treating patients with anaplastic large cell lymphoma, mantle cell lymphoma, or diffuse large B-cell lymphoma that has not responded to previous treatment (refractory) or that has returned after a period of improvement (recurrent). Onalespib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Start Date04 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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62

Literatures (Medical) associated with Onalespib

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.

24 Aug 2023·Cancers

Enhanced Therapeutic Effects of ¹⁷⁷Lu-DOTA-M5A in Combination with Heat Shock Protein 90 Inhibitor Onalespib in Colorectal Cancer Xenografts.

Article

Author: Spangler, Douglas ; Chopra, Saloni ; Nestor, Marika ; Yazaki, Paul J ; Mohajershojai, Tabassom ; Frejd, Fredrik Y

Carcinoembryonic antigen (CEA) has emerged as an attractive target for theranostic applications in colorectal cancers (CRCs). In the present study, the humanized anti-CEA antibody hT84.66-M5A (M5A) was labeled with ¹⁷⁷Lu for potential CRC therapy. Moreover, the novel combination of ¹⁷⁷Lu-DOTA-M5A with the heat shock protein 90 inhibitor onalespib, suggested to mediate radiosensitizing properties, was assessed in vivo for the first time. M5A antibody uptake and therapeutic effects, alone or in combination with onalespib, were assessed in human CRC xenografts and visualized using SPECT/CT imaging. Although both ¹⁷⁷Lu-DOTA-M5A and onalespib monotherapies effectively reduced tumor growth rates, the combination therapy demonstrated the most substantial impact, achieving a fourfold reduction in tumor growth compared to the control group. Median survival increased by 33% compared to ¹⁷⁷Lu-DOTA-M5A alone, and tripled compared to control and onalespib groups. Importantly, combination therapy yielded comparable or superior effects to the double dose of ¹⁷⁷Lu-DOTA-M5A monotherapy. ¹⁷⁷Lu-DOTA-M5A increased apoptotic cell levels, indicating its potential to induce tumor cell death. These findings show promise for ¹⁷⁷Lu-DOTA-M5A as a CRC therapeutic agent, and its combination with onalespib could significantly enhance treatment efficacy. Further in vivo studies are warranted to validate these findings fully and explore the treatment's potential for clinical use.

15 Jun 2023·Cancer

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

Article

Author: Shapiro, Geoffrey I ; Giobbie-Hurder, Anita ; Parikh, Aparna ; Mooradian, Meghan J ; Darville, Lancia N F ; Sullivan, Ryan J ; Chen, Helen X ; Lawrence, Donald P ; Cleary, James M ; Smalley, Keiran S M ; Ivy, Susan Percy ; Koomen, John M ; Buchbinder, Elizabeth I ; Keer, Harold ; Cohen, Justine V

BACKGROUNDCombination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.METHODSCancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.RESULTSTwenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m² on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer.CONCLUSIONSHSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

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.	-
Metastatic castration-resistant prostate cancer	Phase 1	ES	Astex Pharmaceuticals, Inc.	01 Sep 2012
Metastatic castration-resistant prostate cancer	Phase 1	GB	Astex Pharmaceuticals, Inc.	01 Sep 2012
Metastatic castration-resistant prostate cancer	Phase 1	CA	Astex Pharmaceuticals, Inc.	01 Sep 2012
Gastrointestinal Stromal Tumors	Phase 1	US	Astex Pharmaceuticals, Inc.	01 Mar 2011
ALK-positive anaplastic large cell lymphoma	Preclinical	US	National Cancer Institute	04 Apr 2016
Diffuse large B-cell lymphoma refractory	Preclinical	US	National Cancer Institute	04 Apr 2016
Mantle cell lymphoma recurrent	Preclinical	US	National Cancer Institute	04 Apr 2016
Recurrent Transformed B-Cell Non-Hodgkin Lymphoma	Preclinical	US	National Cancer Institute	04 Apr 2016
Refractory Transformed Indolent B-Cell Non-Hodgkin Lymphoma	Preclinical	US	National Cancer Institute	04 Apr 2016

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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))	mdjjcdkgte(uwskwcyjqd) = jzhdueqnob ezwbsvnkdf (bmqfjacazo, bbzjtgflas - uuxggbyxgl) View more	-	16 Oct 2024
	Phase 1		22	Dabrafenib+Trametinib+Onalespib (Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2)	(lptbuwzddw) = kjadbscnhn vhltufzjql (qzpdpdrton, faqnhcufdr - atjhcgkmkn) 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	(hiimajnieb) = yiwbrebxnc npphggabbt (bexaydmbhr, 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	(kfvyzpqaup) = lhafxcsvuk oewxkhwlcx (qiwdwbrxac ) 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)	(rkaxclsktr) = nmtmchtdhc cfjrqrfaot (bbbtxxxrep, zlkrarqrvo - gojplutlzf) View more	-	13 Sep 2022
NCT02572453 (CTgov)	Phase 2		25	Onalespib (Relapsed MCL)	(rkaxclsktr) = crnjvaismx cfjrqrfaot (bbbtxxxrep, mesgvtuapx - papmdbslia) 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	(bebyoytlno) = wywjvvscse cghbjtwoec (ttzxwlkgch, zskfwuwbrf - vqlysciqvm) View more	-	22 Jun 2022
NCT02535338 (NCI 9878, Pubmed \| Clin Lung Cancer) Manual	Phase 1/2	Non-Small Cell Lung Cancer	11	Erlotinib+Onalespib	(akxofwfxfp) = tdjeluvmew foyiaalehj (gddqedibpx, 0.9 - 5.7) View more	Negative	01 Nov 2021
NCT02503709 (Pubmed) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	28	onalespib+AT7519	(wviryuuodu) = onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV kjzkmpjnbn (ndfjxenbkx ) View more	Positive	01 Dec 2020
NCT02097225 (ASCO2020) Manual	Phase 1	BRAF mutation Solid Tumors BRAF V600E Mutation \| BRAF V600K Mutation	22	AT13387+dabrafenib+trametinib	(inpoymwpua) = Dab 150mg [BID/PO], Tram 2mg [QD/PO] and AT1187 260mg/m2 [D1,8,15/IV]. lralrztxxg (dozqcxofzm )	Positive	29 May 2020
NCT02474173 (ESMO2019) Manual	Phase 1	Advanced Triple-Negative Breast Carcinoma	20	paclitaxel+onalespib	(mbsyudnqjl) = One DLT occurred in 1 pt in DL3 (grade 3 nausea, vomiting and abdominal pain) nihlkaldfp (cxuzlgqpbn ) View more	Positive	29 Sep 2019
NCT01685268 (Pubmed \| Clin Cancer Res) Manual	Phase 1/2	Prostatic Cancer	48	prednisone+prednisolone+Onalespib+Abiraterone Acetate	(joeeunxndp) = obyxdqpdjc easnjkhbru (tmfzzxmfda ) View more	Negative	01 Aug 2019