CDK2 inhibitors(Cyclin-dependent kinase 2 inhibitors), CDK4 modulators(Cyclin-dependent kinase 4 modulators), CDK6 inhibitors(Cyclin-dependent kinase 6 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication

Glioblastoma

Inactive Indication

Colonic CancerProstatic Cancer

Originator Organization

University of Gdansk

Active Organization

New York Medical College

Inactive Organization

University of Gdansk

AV Therapeutics, Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with C-1748

100 Translational Medicine associated with C-1748

100 Patents (Medical) associated with C-1748

Literatures (Medical) associated with C-1748

01 Mar 2021·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

A new 1-nitro-9-aminoacridine derivative targeting yeast topoisomerase II able to overcome fluconazole-resistance

Q4 · MEDICINE

Article

Author: Paluszkiewicz, Ewa ; Rząd, Kamila ; Gabriel, Iwona

Fungal resistance remains a significant threat and a leading cause of death worldwide. Thus, overcoming microbial infections have again become a serious clinical problem. Although acridine derivatives are widely analyzed as anticancer agents, only a few reports have demonstrated their antifungal activity. In an effort to develop biologically active antifungals, twelve novel C-857 (9-(2'-hydroxyethylamino)-1-nitroacridine) and C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) derivatives were synthesized. The evaluation of biological properties suggests that starting compounds: C-1748, C-857 and IE3 (2-[(4-methyl-1-nitroacridin-9-yl)amino]ethyl lysinate), IE4 (2-[(1-nitroacridin-9-yl)amino]ethyl lysinate) antifungal mode of action differ from that determined for IE5 (N'-{3-[(4-methyl-1-nitroacridin-9-yl)amino]propyl}lysinamide), IE6 (N'-{3-[(1-nitroacridin-9-yl)amino]propyl}lysinamide) and IE10 (3,3'-Bis-(1-nitroacridin-9-ylamino)-aminoethylaminoethylaminoethylamine). Although MIC values determined for the latter were higher, in contrast to C-857 and C-1748, newly synthesized IE5, IE6 and IE10 reduced C. albicans hyphal growth in different inducing media. Those compounds also exhibited antibiofilm activity, whereas IE10 was the most effective. Moreover, only IE6 exhibited antifungal activity against fluconazole resistant C. albicans strains with MICs values in the range of 16-64 μg mL^-1. Our results also indicate that, in contrast to other analyzed derivatives, novel synthetized compounds IE6 and IE10 with antifungal activity target yeast topoisomerase II activity.

01 Oct 2018·Pharmacological ReportsQ4 · MEDICINE

Drug-drug interaction potential of antitumor acridine agent C-1748: The substrate of UDP-glucuronosyltransferases 2B7, 2B17 and the inhibitor of 1A9 and 2B7

Q4 · MEDICINE

Article

Author: Mazerska, Zofia ; Sominko, Hanna ; Ryska, Izabela ; Bejrowska, Anna ; Mróz, Anna

BACKGROUNDThe compound 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), the promising antitumor agent developed in our laboratory was determined to undergo phase I metabolic pathways. The present studies aimed to know its biotransformation with phase II enzymes - UDP-glucuronosyltransferases (UGTs) and its potential to be engaged in drug-drug interactions arising from the modulation of UGT activity.METHODSUGT-mediated transformations with rat liver (RLM), human liver (HLM), and human intestine (HIM) microsomes and with 10 recombinant human isoenzymes were investigated. Studies on the ability of C-1748 to inhibit UGT were performed with HLM, HT29 colorectal cancer cell homogenate and the selected recombinant UGT isoenzymes. The reactions were monitored using HPLC-UV/Vis method and the C-1748 metabolite structure was determined with ESI-TOF-MS/MS analysis.RESULTSPseudo-molecular ion (m/z 474.1554) and the experiment with β-glucuronidase indicated that O-glucuronide of C-1748 was formed in the presence of microsomal fractions. This reaction was selectively catalyzed by UGT2B7 and 2B17. High inhibitory effect of C-1748 was shown towards isoenzyme UGT1A9 (IC₅₀=39.7μM) and significant but low inhibitory potential was expressed in HT29 cell homogenate (IC₅₀=84.5μM). The mixed-type inhibition mechanism (K_i=17.0μM;K_i'=81.0μM), induced by C-1748 was observed for recombinant UGT1A9 glucuronidation, whereas HT29 cell homogenate resulted in noncompetitive inhibition (K_i=94.6μM).CONCLUSIONSThe observed UGT-mediated metabolism of C-1748 and its ability to inhibit UGT activity should be considered as the potency for drug resistance and drug-drug interactions in the prospective multidrug therapy.

01 Oct 2017·Biochemical PharmacologyQ2 · MEDICINE

The overexpression of CPR and P450 3A4 in pancreatic cancer cells changes the metabolic profile and increases the cytotoxicity and pro-apoptotic activity of acridine antitumor agent, C-1748

Q2 · MEDICINE

Article

Author: Borowa-Mazgaj, Barbara ; Mróz, Anna ; Augustin, Ewa ; Mazerska, Zofia ; Paluszkiewicz, Ewa

Drug resistance is one of the major causes of pancreatic cancer treatment failure. Thus, it is still imperative to develop new active compounds and novel approach to improve drug efficacy. Here we present 9-amino-1-nitroacridine antitumor agent, C-1748, developed in our laboratory, as a candidate for pancreatic cancer treatment. We examined (i) the cellular response of pancreatic cancer cell lines: Panc-1, MiaPaCa-2, BxPC-3 and AsPC-1, differing in expression levels of commonly mutated genes for this cancer type, to C-1748 treatment and (ii) the role of P450 3A4 isoenzyme and cytochrome P450 reductase (CPR) in the modulation of this response. C-1748 exhibited the highest cytotoxic activity against MiaPaCa-2, while AsPC-1 cells were the most resistant (IC₅₀: 0.015, 0.075µM, respectively). A considerable amount of apoptosis was detected in Panc-1 and MiaPaCa-2 cells but only limited apoptosis was observed in AsPC-1 and BxPC-3 cells as indicated by morphological changes and biochemical markers. Furthermore, only AsPC-1 cells underwent senescence. Since AsPC-1 cells were the most resistant to C-1748 as evidenced by the lowest P450 3A4 and CPR protein levels, this cell line was subjected to transient transfection either with P450 3A4 or CPR gene. The overexpression of P450 3A4 or CPR changed the pro-apoptotic activity of C-1748 and sensitized AsPC-1 cells to this drug compared to wild-type cells. However, metabolism was changed significantly only for CPR overexpressing cells. In conclusion, the antitumor effectiveness of C-1748 would be improved by multi-drug therapy with chemotherapeutics, that are able to induce P450 3A4 and/or CPR gene expression.

100 Deals associated with C-1748

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	US	New York Medical College	15 Apr 2012
Colonic Cancer	Preclinical	PL	University of Gdansk	21 Dec 2009
Colonic Cancer	Preclinical	US	AV Therapeutics, Inc.	21 Dec 2009
Prostatic Cancer	Preclinical	US	AV Therapeutics, Inc.	21 Dec 2009
Prostatic Cancer	Discovery	PL	University of Gdansk	21 Dec 2009

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