Delving into the Latest Updates on Rabusertib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Rabusertib (USAN/INN)

+ [1]

Target

Chk1

Mechanism

Chk1 inhibitors(Checkpoint kinase 1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication-

Inactive Indication

Advanced cancerAdvanced Lung Non-Small Cell Carcinomametastatic non-small cell lung cancer+ [3]

Originator Organization

Array BioPharma, Inc.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC18H22BrN5O3

InChIKeySYYBDNPGDKKJDU-ZDUSSCGKSA-N

CAS Registry911222-45-2

The purpose of this study is to assess the effect LY2603618 on a protein [enzyme cytochrome P (CYP) 2D6] which is involved in the metabolic pathway of Desipramine in participants with cancer. This is a drug interaction study so the treatment of the disease will not be the main purpose of the study.
The study involves two single doses of 50 milligrams (mg), 1 tablet by mouth, on Day 1 of Period 1 and 2. In Period 1 Desipramine will be administered alone. In Period 2 Desipramine will be administered in combination with LY2603618. LY2603618 will be administered as a 275mg intravenous (IV) infusion over 1 hour (hr).
Desipramine will be administered at the end of the LY2603618 infusion. Information about any side effects that may occur will also be collected.

Start Date01 Jun 2011

Sponsor / Collaborator

Eli Lilly & Co.

NCT01341457 / CompletedPhase 1

A Phase 1 Dose-Escalation Study of LY2603618 in Combination With Gemcitabine in Japanese Patients With Solid Tumors

The primary objective of this study is to evaluate the safety and tolerability of LY2603618 in combination with the standard dose of gemcitabine up to the global recommended dose of LY2603618 in Japanese participants with solid advanced or metastatic tumors.

Start Date01 May 2011

Sponsor / Collaborator

Eli Lilly & Co.

NCT01139775 / CompletedPhase 1/2

A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination With Pemetrexed and Cisplatin in Patients With Stage IV Non-small Cell Lung Cancer

LY2603618 is a selective inhibitor of the deoxyribonucleic acid (DNA) damage checkpoint kinase 1 (CHK1). It was being developed as a chemotherapeutic-enhancing agent in the treatment of cancer. Phase 1 studies have shown the feasibility of combining LY2603618 with either gemcitabine or pemetrexed. The objective of this study was to find the dose of LY2603618 that can be safely combined with standard doses of pemetrexed and cisplatin and to test if this triplet offered a significant improvement in progression-free survival (PFS) in participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) in the first-line of palliative treatment.

Start Date01 Feb 2011

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Rabusertib

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100 Translational Medicine associated with Rabusertib

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100 Patents (Medical) associated with Rabusertib

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34

Literatures (Medical) associated with Rabusertib

01 Oct 2023·Gynecologic oncology

Metronomic dosing of ovarian cancer cells with the ATR inhibitor AZD6738 leads to loss of CDC25A expression and resistance to ATRi treatment.

Article

Author: Wilkerson, Matthew D ; Conrads, Thomas P ; Kim, Hong Im ; Tarney, Christopher M ; Darcy, Kathleen M ; Litzi, Tracy ; Bakkenist, Christopher J ; Tommarello, Domenic ; Abulez, Tamara ; Teng, Pang-Ning ; Bateman, Nicholas W ; Hood, Brian L ; Conrads, Kelly A ; Zhang, Xijun ; Dalgard, Clifton L ; Maxwell, G Larry ; Phippen, Neil T ; Risinger, John I ; Ao, Wei

OBJECTIVEATR kinase inhibitors promote cell killing by inducing replication stress and through potentiation of genotoxic agents in gynecologic cancer cells. To explore mechanisms of acquired resistance to ATRi in ovarian cancer, we characterized ATRi-resistant ovarian cancer cells generated by metronomic dosing with the clinical ATR inhibitor AZD6738.METHODSATRi-resistant ovarian cancer cells (OVCAR3 and OV90) were generated by dosing with AZD6738 and assessed for sensitivity to Chk1i (LY2603618), PARPi (Olaparib) and combination with cisplatin or a CDK4/6 inhibitor (Palbociclib). Models were characterized by diverse methods including silencing CDC25A in OV90 cells and assessing impact on ATRi response. Serum proteomic analysis of ATRi-resistant OV90 xenografts was performed to identify circulating biomarker candidates of ATRi-resistance.RESULTSAZD6738-resistant cell lines are refractory to LY2603618, but not to Olaparib or combinations with cisplatin. Cell cycle analyses showed ATRi-resistant cells exhibit G1/S arrest following AZD6738 treatment. Accordingly, combination with Palbociclib confers resistance to AZD6738. AZD6738-resistant cells exhibit altered abundances of G1/S phase regulatory proteins, including loss of CDC25A in AZD6738-resistant OV90 cells. Silencing of CDC25A in OV90 cells confers resistance to AZD6738. Serum proteomics from AZD6738-resistant OV90 xenografts identified Vitamin D-Binding Protein (GC), Apolipoprotein E (APOE) and A1 (APOA1) as significantly elevated in AZD6738-resistant backgrounds.CONCLUSIONSWe show that metronomic dosing of ovarian cancer cells with AZD6738 results in resistance to ATR/ Chk1 inhibitors, that loss of CDC25A expression represents a mechanism of resistance to ATRi treatment in ovarian cancer cells and identify several circulating biomarker candidates of CDC25A low, AZD6738-resistant ovarian cancer cells.

01 Aug 2023·Cancer Letters

Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1

Article

Author: Nair, Sindhu ; Venere, Monica ; DeWees, Todd ; Corrales-Guerrero, Sergio ; Yang, Linlin ; Castro-Aceituno, Veronica ; Yoon, Stephanie ; Williams, Terence M ; Shen, Changxian ; Feng, Haihua ; Cui, Tiantian

Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.

31 Dec 2022·Cancer Biology & TherapyQ3 · MEDICINE

Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion

Q3 · MEDICINE

Article

Author: Li, Meng-Zhu ; Chen, Hua-Dong ; He, Jin-Xue ; Wang, Li-Min ; Miao, Ze-Hong ; Guo, Ne ; Song, Shan-Shan

PARP1 and Chk1 inhibitors have been shown to be synergistic in different cancer models in relatively short time treatment modes. However, the consequences of long-term/repeated treatments with the combinations in cancer models remain unclear. In this study, the synergistic cytotoxicity of their combinations in 8 tumor cell lines was confirmed in a 7-day exposure mode. Then, pancreatic Capan-1 cells were repeatedly treated with the PARP1 inhibitor olaparib, the Chk1 inhibitor rabusertib or their combination for 211-214 days, during which the changes in drug sensitivity were monitored at a 35-day interval. Unexpectedly, among the 3 treatment modes, the combination treatments resulted in the highest-grade resistance to Chk1 (~14.6 fold) and PARP1 (~420.2 fold) inhibitors, respectively. Consistently, G2/M arrest and apoptosis decreased significantly in the resulting resistant variants exposed to olaparib. All 3 resistant variants also unexpectedly obtained enhanced migratory and invasive capabilities. Moreover, the combination treatments resulted in increased migration and invasion than olaparib alone. The expression of 124 genes changed significantly in all the resistant variants. We further demonstrate that activating CXCL3-ERK1/2 signaling might contribute to the enhanced migratory capabilities rather than the acquired drug resistance. Our findings indicate that repeated treatments with the rabusertib/olaparib combination result in increased drug resistance and a more aggressive cell phenotype than those with either single agent, providing new clues for future clinical anticancer tests of PARP1 and Chk1 inhibitor combinations.

100 Deals associated with Rabusertib

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External Link

KEGG	Wiki	ATC	Drug Bank
D10397	-	-	DB11662

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Lung Non-Small Cell Carcinoma	Phase 2	TW	Eli Lilly & Co.	01 Nov 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	KR	Eli Lilly & Co.	01 Nov 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	IT	Eli Lilly & Co.	01 Nov 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	US	Eli Lilly & Co.	01 Nov 2009
Pancreatic Cancer	Phase 2	RO	Eli Lilly & Co.	01 Feb 2009
Pancreatic Cancer	Phase 2	ES	Eli Lilly & Co.	01 Feb 2009
Pancreatic Cancer	Phase 2	IT	Eli Lilly & Co.	01 Feb 2009
Pancreatic Cancer	Phase 2	DE	Eli Lilly & Co.	01 Feb 2009
Pancreatic Cancer	Phase 2	US	Eli Lilly & Co.	01 Feb 2009
Pancreatic Cancer	Phase 1	NL	Eli Lilly & Co.	01 Feb 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01341457 (CTgov)	Phase 1	Solid tumor	17	gemcitabine+LY2603618	nuztxuaqbz(ftfvniixcf) = zoxcgdsmwv kpdbacnoua (uvkvkzdvfn, ygnfqnjolf - pvabhmanpv) View more	-	01 Mar 2019
NCT01296568 (CTgov)	Phase 1	Metastatic Solid Tumor \| Advanced cancer	3	14C]LY2603618 ([^14C]LY2603618)	opgddglkmb(korglrlgoa) = berdycryog rsawaghajf (agaugfcnja, ezkptckifs - favsspiwtm) View more	-	25 Oct 2018
				[^14C]LY2603618+gemcitabine+LY2603618 (Entire Study Population)	cblxlbvwyy(jzgrwfvdxk) = zaxjmofokf uxkifjimps (icczsosxpg, rcfbffways - nrzehmyyvt) View more
NCT01358968 (CTgov)	Phase 1	Neoplasms	20	Desipramine+Gemcitabine+LY2603618+Pemetrexed	uovuroqqto(egnjomzuqc) = gjwqumjexa xbwwxbrupo (zdkjwwukcp, yntlsdvmav - svttbobcko) View more	-	25 Oct 2018
NCT00415636 (CTgov)	Phase 1	Neoplasms	31	IC83/LY2603618+Pemetrexed (LY2603618 40 mg/m^2 (4.5-hour Infusion))	fenrmtvoyo(vehzldzuvb) = wvadihdkem ccxoffufpf (ewyyncoszo, qofwwtkyog - pllipybjnp) View more	-	19 Oct 2018
				IC83/LY2603618+Pemetrexed (LY2603618 40 mg/m^2 (1-hour Infusion))	fenrmtvoyo(vehzldzuvb) = wpaqkggriz ccxoffufpf (ewyyncoszo, qtqmqwyvcy - xclfkkfhac) View more
NCT01139775 (CTgov)	Phase 1/2	metastatic non-small cell lung cancer	76	cisplatin+LY2603618+Pemetrexed (Phase 2: Pemetrexed + Cisplatin + LY2603618)	uhuwtubhri(ykcvcwsfnd) = nrnareljvd eyrmxocosc (sxgkiaykqb, lhqkhusygq - wyvfrvzrmr) View more	-	18 May 2018
				cisplatin+Pemetrexed (Phase 2: Pemetrexed + Cisplatin)	uhuwtubhri(ykcvcwsfnd) = qulqubwzmf eyrmxocosc (sxgkiaykqb, pnadvwczbc - nvnebmtwsy) View more
NCT00839332 (CTgov)	Phase 1/2	Pancreatic Cancer	157	Gemcitabine+LY2603618 (Phase 1: LY2603618 + Gemcitabine)	fiuprovfup(joryarxhjt) = uvfyewvtdo uasjqphsko (vlvkrydnyh, jxjeuytvyg - edtckfyfjv) View more	-	17 Apr 2018
				Gemcitabine+LY2603618 (Phase 2: LY2603618 + Gemcitabine)	qkvyymdomt(kgyljxgpcf) = dpelpilmiy nfkrhwagry (jalqnvtykx, uojsndervx - huexklpbll) View more
NCT00988858 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	55	LY2603618+pemetrexed	iuiqdslpnl(bdcclzanmt) = hwlncelxlh kwxphnfbxh (vemaauebfz, gwfvvrqvkf - tneiwozcmo) View more	-	15 Aug 2017
NCT01139775 (Pubmed \| Lung Cancer) Manual	Phase 2	Non-squamous non-small cell lung cancer	62	Pemetrexed+Cisplatin+LY2603618	(sjynjtdccs) = rmtwsfrxns ajuooeubhw (lmdfxdljtl, 4 - 7.1) View more	Negative	01 Jun 2017
				Pemetrexed+Cisplatin+Placebo	(sjynjtdccs) = ixdyoykayl ajuooeubhw (lmdfxdljtl, 1.3 - 2.9) View more
NCT00988858 (Pubmed \| Invest New Drugs) Manual	Phase 2	Non-Small Cell Lung Cancer Second line	55	pemetrexed+LY2603618	(cgongcvuel) = awfqdqhbbe glrehxreip (vieutzycnn, 3.7 - 18.2) View more	Negative	01 Oct 2016