Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?

ABSTRACT

Introduction

Cancer continues to be a big threat and its treatment is a huge challenge among the medical fraternity. Conventional anti-cancer agents are losing their efficiency which highlights the need to introduce new anti-cancer entities for treating this complex disease. A hybrid molecule has a tendency to act through varied modes of action on multiple targets at a given time. Thus, there is the significant scope with hybrid compounds to tackle the existing limitations of cancer chemotherapy.

Area Covered

This perspective describes the most significant hybrids that spring hope in the field of cancer chemotherapy. Several hybrids with anti-proliferative/anti-tumor properties currently approved or in clinical development are outlined, along with a description of their mechanism of action and identified drug targets.

Expert opinion

The success of molecular hybridization in cancer chemotherapy is quite evident by the number of molecules entering into clinical trials and/or have entered the drug market over the past decade. Indeed, the recent advancements and co-ordinations in the interface between chemistry, biology, and pharmacology will help further the advancement of hybrid chemotherapeutics in the future.

List of abbreviations: Deoxyribonucleic acid, DNA; national cancer institute, NCI; peripheral blood mononuclear cells, PBMC; food and drug administration, FDA; histone deacetylase, HDAC; epidermal growth factor receptor, EGFR; vascular endothelial growth factor receptor, VEGFR; suberoylanilide hydroxamic acid, SAHA; farnesyltransferase inhibitor, FTI; adenosine triphosphate, ATP; Tamoxifen, TAM; selective estrogen receptor modulator, SERM; structure activity relationship, SAR; estrogen receptor, ER; lethal dose, LD; half maximal growth inhibitory concentration, GI₅₀; half maximal inhibitory concentration, IC₅₀.

KEYWORDS:

• Cancer
• hybrid molecules
• drug design
• structure-activity relationship
• clinical trials
• approved drugs

Article highlights

• Cancer, the second leading cause of death worldwide, poses an immense socio-economic burden.

• The success of single-agent chemotherapeutics is hampered by emergence of resistance to multiple structurally and functionally unrelated drugs.

• Drug hybridization, involving linking of two or more bioactive pharmacophores has emerged as a significant approach.

• Hybrid chemotherapeutics with the ability to modulate multiple targets simultaneously can overcome the existing limitations in cancer treatment.

• A number of hybrid compounds are either approved as drugs and/or in different phases of clinical development proving its potential in anticancer drug discovery regimens.

This box summarizes key points contained in the article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Declaration of interest

Shalini has received an Inspire Fellowship from the Department of Science and Technology, of the Government of India (award number IF 160,180). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Shalini received doctoral fellowship (Shalini, IF160180) by Department of Science and Technology (DST), New Delhi, India, under INSPIRE programme. VK acknowledges the Council of Scientific and Industrial Research (CSIR), New Delhi, for financial assistance (Grant No. 02(0293)/17/EMR-II).