Delving into the Latest Updates on Pixantrone Dimaleate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

6,9-bis((2-aminoethyl)amino)benzo(g)isoquinoline-5,10-dione, Pixantrone, Pixantrone dimaleate (USAN)

+ [7]

Target

Top II

Mechanism

Top II inhibitors(Topoisomerase II inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

Non-Hodgkin Lymphoma

Inactive Indication

Aggressive B-Cell Non-Hodgkin LymphomaB-cell lymphoma refractoryDiffuse Large B-Cell Lymphoma+ [7]

Originator Organization

Cell Therapy Ltd.

Active Organization

Les Laboratoires Servier SAS

Inactive Organization

CTI BioPharma Corp.

Drug Highest PhaseApproved

First Approval Date

EU (10 May 2012),

Non-Hodgkin Lymphoma

Regulation-

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Structure

Molecular FormulaC25H27N5O10

InChIKeySVAGFBGXEWPNJC-SPIKMXEPSA-N

CAS Registry144675-97-8

View All Structures (2)

BACKGROUNDMini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation.METHODSMolecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo.RESULTSPixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety.CONCLUSIONThese findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic.

01 Jun 2024·Journal of Oncology Pharmacy Practice

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy

Article

Author: Almasi, Jannik ; Krämer, Irene ; Knoll, Laura ; Thiesen, Judith

Background Risk factors for aseptic preparation of parenteral medicines encompass the growth-promoting nature of the preparation. Although many aqueous parenteral preparations do not have growth-promoting properties, inadvertently introduced microorganisms may remain viable. Knowledge about the viability of microorganisms in parenteral preparations can add useful information for assigning shelf life to preparations used to treat cancer patients. Aim The aim of the study was to assess the viability of four different facultative pathogenic microorganisms in 20 ready-to-administer parenteral preparations aseptically prepared in hospital pharmacies. Methods Samples of 20 different biologics and small molecules for systemic anti-cancer therapy were inoculated either with different bacteria (i.e., Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium) or with Candida albicans suspension. The resulting test concentrations were 104–105 microorganisms per mL. Aliquots of inoculated test solutions were transferred in duplicate to tryptic soy agar plates at the time points 0, 4, 24, 48, 144 h. The plates were incubated for 24 h (bacterial strains) and 72 h ( C. albicans) at 37 °C and colony forming units (CFUs) were counted. Results In most test solutions, especially in monoclonal antibody solutions, increased CFU counts of P. aeruginosa and unchanged or increased CFU counts of E. faecium and S. aureus were registered . Pronounced nutritive properties of monoclonal antibodies and filgrastim were not registered. Azacitidine, pixantrone and vinflunine containing test solutions revealed species-specific bacteriostatic and even bactericidal activity. All test solutions, except nivolumab and pixantrone containing solutions, showed constant or increasing CFU counts of C. albicans after incubation. Conclusion Viability of the selected pathogenic microorganisms was retained in most of the tested biological and small molecule preparations used to treat cancer patients. Therefore, in pharmacy departments strict aseptic conditions should be regarded and the lack of antimicrobial activity should be considered when assigning shelf life to RTA parenteral preparations.

01 Jun 2024·Cancer Letters

Oncogenic functions and therapeutic potentials of targeted inhibition of SMARCAL1 in small cell lung cancer

Article

Author: Wang, Gui-Zhen ; Sun, Bei-Bei ; Guo, Hua ; Han, Si-Chong ; Yang, Fu-Ying ; Liu, Jinsong ; Zhou, Guang-Biao ; Liu, Yu-Tao

Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by high frequency loss-of-function mutations in tumor suppressors with a lack of targeted therapy due to absence of high frequency gain-of-function abnormalities in oncogenes. SMARCAL1 is a member of the ATP-dependent chromatin remodeling protein SNF2 family that plays critical roles in DNA damage repair and genome stability maintenance. Here, we showed that SMARCAL1 was overexpressed in SCLC patient samples and was inversely associated with overall survival of the patients. SMARCAL1 was required for SCLC cell proliferation and genome integrity. Mass spectrometry revealed that PAR6B was a downstream SMARCAL1 signal molecule which rescued inhibitory effects caused by silencing of SMARCAL1. By screening of 36 FDA-approved clinically available agents related to DNA damage repair, we found that an aza-anthracenedione, pixantrone, was a potent SMARCAL1 inhibitor which suppressed the expression of SMARCAL1 and PAR6B at protein level. Pixantrone caused DNA damage and exhibited inhibitory effects on SCLC cells in vitro and in a patient-derived xenograft mouse model. These results indicated that SMARCAL1 functions as an oncogene in SCLC, and pixantrone as a SMARCAL1 inhibitor bears therapeutic potentials in this deadly disease.

100 Deals associated with Pixantrone Dimaleate

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External Link

KEGG	Wiki	ATC	Drug Bank
D09654	Pixantrone Dimaleate	L01DB11	DB06193

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Non-Hodgkin Lymphoma	NO	Les Laboratoires Servier SAS	10 May 2012
Non-Hodgkin Lymphoma	IS	Les Laboratoires Servier SAS	10 May 2012
Non-Hodgkin Lymphoma	EU	Les Laboratoires Servier SAS	10 May 2012
Non-Hodgkin Lymphoma	LI	Les Laboratoires Servier SAS	10 May 2012

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Non-Hodgkin Lymphoma	Phase 3	AR	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	FR	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	RU	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	IN	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	PE	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	RO	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	MX	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	UY	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Phase 3	GB	CTI BioPharma Corp.	01 Jul 2004
Recurrent Non-Hodgkin Lymphoma	Discovery	BG	CTI BioPharma Corp.	01 Jul 2004

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00268853 (RAPID, CTgov)	Phase 2	Diffuse Large B-Cell Lymphoma	124	rituximab+Cyclophosphamide+Prednisone+pixantrone+CPOP-R+vincristine (CPOP-R)	(rhgqdzzocv) = ltowhaghtm gxlxpsxzot (lmphedtetu, dekrruedym - qlzlwwcshy) View more	-	30 May 2024
				rituximab+Cyclophosphamide+Prednisone+doxorubicin+vincristine+CHOP-R (CHOP-R)	(rhgqdzzocv) = bticovyisp gxlxpsxzot (lmphedtetu, sslcosnhuz - lmcfkghuya) View more
PIVeR (ICML2023)	Phase 2	Refractory Aggressive Non-Hodgkin Lymphoma CD20+	74	Pixantrone+Rituximab+Ifosfamide+Etoposide	foumvxdsej(rzbiuahjjd) = suyldjvfgz ykiyhvtdih (tedtzybdek, 49.2% - 69.1%) View more	Positive	09 Jun 2023
NCT01086605 (NCCTG N1031 \| Alliance, Pubmed \| Oncologist) Manual	Phase 2	Metastatic breast cancer	45	Pixantrone (group A)	(eulbpohdmz) = izdxmibche hyeygmjezh (tfaflffksi )	Negative	21 Apr 2022
				Pixantrone (group B)	(eulbpohdmz) = gmiadgwjoe hyeygmjezh (tfaflffksi )
NCT01321541 (PIX306 \| PIX-R, CTgov)	Phase 3	Follicular Lymphoma \| Aggressive B-Cell Non-Hodgkin Lymphoma \| Diffuse Large B-Cell Lymphoma	312	Pixantrone+Rituximab (Pixantrone + Rituximab)	(assfldjvhz) = myvzscvzsk okljmenljf (kcsengextz, ijfgwkcshd - ziqkkifjgz) View more	-	19 Nov 2021
				Gemcitabine+Rituximab (Gemcitabine + Rituximab)	(assfldjvhz) = hljofoywry okljmenljf (kcsengextz, wnfaitrmks - pqeszqcktp) View more
ICML2021	Not Applicable	Diffuse Large B-Cell Lymphoma Third line	27	Pixantrone	qtykpmhzno(swrqcqiehh) = No patients had grade IV adverse events, which caused drug discontinuation or cardiotoxicity almjooyqfu (egwexyruzg )	Positive	17 Jun 2021
NCT01321541 (PIX306, Pubmed) Manual	Phase 3	Aggressive B-Cell Non-Hodgkin Lymphoma	312	Pixantrone+rituximab	(ydfkmeacdh) = mfpagqvvft rbinmcjeza (llrruxnmcf, 5.2 - 8.4) View more	Negative	01 Jan 2020
				gemcitabine+rituximab	(ydfkmeacdh) = xcikosojuq rbinmcjeza (llrruxnmcf, 4.4 - 8.1) View more
NCT01491841 (BRP, CTgov)	Phase 1	B-cell lymphoma refractory	33	Pegfilgrastim+Bendamustine+Pixantrone+Rituximab (Phase 1: Pixantrone, 55mg/m^2)	(xnqfbjelpl) = rnsgovxavo jbslkpekxc (bkeuusugtj, xcwbxyifbk - vvlscorpii) View more	-	14 Jun 2019
				Pegfilgrastim+Bendamustine+Pixantrone+Rituximab (Phase 1: Pixantrone, 85mg/m^2)	(xnqfbjelpl) = uyzamsuuyf jbslkpekxc (bkeuusugtj, ikdioqthoj - ftyjbozamg) View more
EUCTR2015-000758-39-SE (PREBEN/PEBEN, ICML2017)	Phase 1/2	T-Cell Lymphoma \| B-Cell Lymphoma CD20+	12	Pixantrone 50 mg/m2	(agzaaigubt) = htbanihfdx cicnqqtext (cnywsqnotq )	Positive	07 Jun 2017
				Etoposide 100 mg	(agzaaigubt) = pywmupkijv cicnqqtext (cnywsqnotq )
NCT01086605 (NCCTG N1031, Alliance, CTgov)	Phase 2	Metastatic breast cancer	46	Pixantrone (Arm I/Group A (Pixantrone IV Day 1))	iiwpafaxsq(zyupyptxco) = gamsvqxvgz rhaushrirj (xqciwlyacm, lrokwffpmg - mnvtsfubhd) View more	-	23 Feb 2017
				Pixantrone (Arm II/Group B (Pixantrone IV Days 1, 8, and 15))	iiwpafaxsq(zyupyptxco) = unxmimfjod rhaushrirj (xqciwlyacm, fyqdovipga - rwiavaydgp) View more
PIXAMS (AAN2014)	Phase 1/2	Multiple Sclerosis	18	Pixantrone	(xrapoeidpa) = dtpsqeuytd qftiktodrl (ckhvqkxcyv, 6.48) View more	-	08 Apr 2014