Delving into the Latest Updates on Elacridar with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Elacridar hydrochloride (USAN)

+ [6]

Target

ABCG2 x P-gp

Action

inhibitors

Mechanism

ABCG2 inhibitors(Broad substrate specificity ATP-binding cassette transporter ABCG2 inhibitors), P-gp inhibitors(P-glycoprotein 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

Chiba University

Inactive Organization

GSK Plc

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC34H33N3O5

InChIKeyOSFCMRGOZNQUSW-UHFFFAOYSA-N

CAS Registry143664-11-3

The multidrug transporter P-glycoprotein (P-gp), is pivotal in exporting various chem. dissimilar amphipathic compounds including anti-cancer drugs, thus causing multidrug resistance during cancer treatment.P-gp is composed of two transmembrane domains (TMDs), each containing six homologous transmembrane helixes (TMHs).Among these helixes, TMH 6 and 12 align oppositely, lining a drug-binding pocket in the transmembrane region which acts as a pathway for drug efflux.Previously, specific mutations within TMH 6 and 12 resulted in loss of substrate efflux and altered the transport direction from efflux to uptake for some substrates.This suggested a regulatory switch that governs the direction of transport.The authors sought to elucidate the mechanism of switch region modulation of the uptake function by engineering several mutants via substituting specific residues in TMH 6 and 12.The alanine substitution of four residues (V974, L975, V977, and F978) within the upper region of TMH 12, along with three residues (V334, F336, and F343) within TMH 6, was sufficient to convert P-gp from an efflux to an uptake pump.Addnl. mutagenesis of the residues in the middle region of TMH 12 revealed that the uptake function, like efflux, is reversible.Further studies, including mol. dynamics simulations, revealed that the switch region appears to act during the substrate translocation step.The authors propose that the switch region in TMH 6 and 12, which modulates the direction of transport by P-gp, provides a novel approach to selectively target P-gp-expressing cancer cells.

09 Jan 2025·Journal of Medicinal Chemistry

Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives

Article

Author: Sopper, Sieghart ; Puhr, Martin ; Schoepf, Anna M. ; Heidegger, Isabel ; Federspiel, Martin ; Pircher, Andreas ; Salcher, Stefan ; Wolf, Dominik ; Hotze, Madlen ; Kwiatkowski, Marcel ; Gust, Ronald ; Gebhart, Maximilian

The present structure-activity relationship study investigates the development of novel chemosensitizers targeting therapy-resistant cancer stem cells (CSCs). We used 4'-((2-propyl-1H-benzo[d]imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from the angiotensin II type 1 receptor blocker telmisartan, as a lead structure, demonstrating that the biphenyl moiety is essential for chemosensitizing activity. Introducing a methyl carboxylate or carboxamide instead of the COOH-group significantly enhanced this effect, leading to the development of highly potent compounds. These novel, noncytotoxic chemosensitizers effectively target CSCs and overcome drug resistance by interfering with CSC persistence mechanisms─hyperactivated STAT5 signaling and increased drug transporter activity─with demonstrated efficacy in leukemia, ovarian, and prostate cancers. The carboxamide of telmisartan (telmi-amide, 7c) significantly reduced tumor growth in an imatinib-resistant leukemia xenograft model, both as monotherapy and combined with imatinib, showing promising oral bioavailability and tolerability. In summary, telmisartan derivatives act as effective chemosensitizers and offer an innovative strategy for targeting CSCs in various malignant diseases.

01 Dec 2024·European Journal of Medicinal Chemistry

Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect

Article

Author: Zhao, Jiangyan ; Tan, Zhoupeng ; Gu, Xiaoke ; Li, Zheng ; Yuan, Weiqun ; Feng, Hao ; Sun, Shuang ; Niu, Mingshan ; Qiu, Jingying ; Wu, Yiqing ; Zeng, Meifeng

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.79 vs. 64.41). Further investigation indicated that 7i dose-dependently inhibited P-gp function, without affecting its expression. CETSA results illustrated that 7i could obviously improve P-gp stability, suggesting its high affinity with P-gp. Molecular docking analysis revealed that 7i fit well into P-gp's binding pocket, thus displaying potent reversal effect on P-gp-mediated tumor MDR Optical properties evaluation confirmed that azo-containing 7i can undergo reversible changes in the cis and trans configurations under the irradiation of 365 nm and 520 nm wavelength of light. Notably, the configuration change of azo might affect the MDR-reversal potency, and cis-7i has a lower RF value than trans-7i (122.70 vs. 142.79), suggesting that development of photoswitchable P-gp inhibitors might be a novel strategy to reduce the systemic toxicity caused by indiscriminate inhibition of P-gp by traditional inhibitors. Collectively, 7i, as a novel P-gp inhibitor, warranted further investigation.

100 Deals associated with Elacridar

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External Link

KEGG	Wiki	ATC	Drug Bank
D03968	-	-	DB04881

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Europe	-	-
Neoplasms	Preclinical	-	GSK Plc	-
Neoplasms	Preclinical	United States	-	-
Neoplasms	Preclinical	Canada	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


P10.21.A (EANO2023)	Not Applicable	Brain Cancer	-	Elacridar	nbvligoeqn(qjlctwntek) = ivweaioxwc peqepihbph (tbojdzzhxj )	-	08 Sep 2023
EANM2016	Not Applicable	P-glycoprotein	3	Elacridar	vulyxwdwsx(rtvoeihxjk) = pjjtmhkfoi lkdkiwefmt (dmdhwcooyq )	Positive	21 Sep 2016
EANM2016	Not Applicable	P-glycoprotein	3	High-dose Erlotinib	vulyxwdwsx(rtvoeihxjk) = rrdhjybapg lkdkiwefmt (dmdhwcooyq )	Positive	21 Sep 2016
SNMMI2016	Not Applicable	-	-	High dose erlotinib	dtilelgrtn(wwktteuhln) = bkiyiyeaqu udwniieigx (edjbcfvrcc, 0.03)	-	24 May 2016
SNMMI2016	Not Applicable	-	-	Elacridar	dtilelgrtn(wwktteuhln) = ypttqzwyqg udwniieigx (edjbcfvrcc, 0.35)	-	24 May 2016
ASCO2004	Phase 1	Advanced cancer	23	Topotecan 2 mg + Elacridar 100 mg	pknmwqfmxb(tdpqtyxlpr) = DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. hgxmkqwdxj (ihevjapkvb ) View more	-	15 Jul 2004