A Quinquennial Review of Potent LSD1 Inhibitors Explored for the Treatment of Different Cancers, with Special Focus on SAR Studies

Author:

Sheikh Khursheed Ahmad1,Iqubal Ashif2,Alam Mohammad Mumtaz1,Akhter Mymoona1,Khan Mohammad Ahmed2,Ehtaishamul Haque Syed2,Parvez Suhel3,Jahangir Umar4,Amir Mohammad1,Khanna Suruchi2,Shaquiquzzaman Mohammad1

Affiliation:

1. Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India

2. Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India

3. Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India

4. Department of Amraaz-e-Jild wa Tazeeniyat, School of Unani Medical Education & Research, Jamia Hamdard, New Delhi, 110062, India

Abstract

Abstract: Cancer bears a significant share of global mortality. The enzyme Lysine Specific Demethylase 1 (LSD1, also known as KDM1A), since its discovery in 2004, has captured the attention of cancer researchers due to its overexpression in several cancers like acute myeloid leukaemia (AML), solid tumours, etc. The Lysine Specific Demethylase (LSD1) downregulation is reported to have an effect on cancer proliferation, migration, and invasion. Therefore, research to discover safer and more potent LSD1 inhibitors can pave the way for the development of better cancer therapeutics. These efforts have resulted in the synthesis of many types of derivatives containing diverse structural nuclei. The present manuscript describes the role of Lysine Specific Demethylase 1 (LSD1) in carcinogenesis, reviews the LSD1 inhibitors explored in the past five years and discusses their comprehensive structural activity characteristics apart from the thorough description of LSD1. Besides, the potential challenges, opportunities, and future perspectives in the development of LSD1 inhibitors are also discussed. The review suggests that tranylcypromine derivatives are the most promising potent LSD1 inhibitors, followed by triazole and pyrimidine derivatives with IC50 values in the nanomolar and sub-micromolar range. A number of potent LSD1 inhibitors derived from natural sources like resveratrol, protoberberine alkaloids, curcumin, etc. are also discussed. The structural-activity relationships discussed in the manuscript can be exploited to design potent and relatively safer LSD1 inhibitors as anticancer agents.

Funder

DST-SERB

Publisher

Bentham Science Publishers Ltd.

Subject

Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry

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