Drug conjugates—an emerging approach to treat breast cancer

Abstract

Breast cancer treatment using a single drug is associated with a high failure rate due, in part, to the heterogeneity of drug response within individuals, nonspecific target action, drug toxicity, and/or development of resistance. Use of dual‐drug therapies, including drug conjugates, may help overcome some of these roadblocks by more selective targeting of the cancer cell and by acting at multiple drug targets rather than one. Drug‐conjugate approaches include linking drugs to antibodies (antibody‐drug conjugates), radionuclides (radioimmunoconjugates), nanoparticles (nanoparticle‐drug conjugates), or to other drugs (drug‐drug conjugates). Although all of these conjugates might be designed as effective treatments against breast cancer, the focus of this review will be on drug‐drug conjugates because of the increase in versatility of these types of drugs with respect to mode of action at the level of the cancer cell either by creating a novel pharmacophore or by increasing the potency and/or efficacy of the drugs’ effects at their respective molecular targets. The development, synthesis, and pharmacological characteristics of drug‐drug conjugates will be discussed in the context of breast cancer with the hope of enhancing drug efficacy and reducing toxicities to improve patient quality of life.

Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs

“…Melatonin-tamoxifen drug conjugates were recently reported as promising drugs for the prevention and treatment of BC without tamoxifen's untoward side effects on the uterus (Witt-Enderby et al, 2014;Hasan et al, 2018). The drug conjugate, C5 (6-[[4-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy]ethylmethylamino]-N-[2-(5-methoxy-1H-indole-3-yl)ethyl]hexanamide), with a spacer of five CH 2 groups was reported in the patent (Witt-Enderby et al, 2014).…”

“…To assess the influence of spacer length and based on the commercial availability of the alkylating agents Br(CH 2 )nCO 2 Me, the following drug conjugates were additionally synthesized: C2 (3- [[4-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy]ethylmethylamino]-N-[2-(5-methoxy-1H-indole-3yl)ethyl]propionamide; n 5 2, shorter spacer), C4 (5-[[4-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy]ethylmethylamino]-N-[2-(5-methoxy-1H-indole-3-yl)ethyl]pentanamide; n 5 4, spacer of a similar length), and C9 (10-[[4-[4-[(1Z)-1,2-diphenyl-1buten-1-yl]phenoxy]ethylmethylamino]-N-[2-(5-methoxy-1Hindole-3-yl)ethyl]decanamide) and C15 (16-[[4-[4-[(1Z)-1,2diphenyl-1-buten-1-yl]phenoxy]ethylmethylamino]-N-[2-(5-methoxy-1H-indole-3-yl)ethyl]hexadecanamide; n 5 9 and 15, respectively; longer spacers). Drug conjugates are emerging as novel anticancer agents, as reviewed previously (Hasan et al, 2018). Benefits of using drug conjugates lie in their ability to modulate diverse targets (receptors and/or intracellular signaling proteins), which has been shown to increase their efficacy as anticancer agents and may also prevent drug resistance and toxicity (Hasan et al, 2018).…”

“…Drug conjugates are emerging as novel anticancer agents, as reviewed previously (Hasan et al, 2018). Benefits of using drug conjugates lie in their ability to modulate diverse targets (receptors and/or intracellular signaling proteins), which has been shown to increase their efficacy as anticancer agents and may also prevent drug resistance and toxicity (Hasan et al, 2018). In this study, we examined a series of melatonin and tamoxifen drug conjugates linked by carbon chains of varying lengths-C2, C4, C5, C9, and C15-against BC cells that express ERs (e.g., MCF-7) and TamR cells, in human epidermal growth factor receptor 2 (HER2)-expressing BC such as mouse mammary carcinoma (MMC) cells, and in triple-negative breast cancer (TNBC) cells (e.g., MDA-MB-231 and BT-549).…”

Chebulinic acid inhibits MDA‐MB‐231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy

“…However, majority of the treatment modalities are associated with significant toxicity and side effects. (Hasan, Leak, Stratford, Zlotos, & Witt‐Enderby, 2018).…”

Synthesis and anti‐inflammatory effects of novel emodin derivatives bearing azole moieties

“…Azole‐based compounds possess good anti‐inflammatory activity with improved safety profiles . We designed a series of novel emodin azole derivatives by merging the triazole/imidazole scaffold with emodin nucleus using the hybrid approach and expected to gain improved bioavailability, and additive or synergistic actions in anti‐inflammatory activity . The synthesized compounds were in vitro assayed for anti‐inflammatory activity by measuring LPS‐induced NO production.…”