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


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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.

About the authors

Khursheed Sheikh

Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Ashif Iqubal

Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Mohammad Alam

Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard

Author for correspondence.
Email: info@benthamscience.net

Mymoona Akhter

Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research,, Jamia Hamdard

Email: info@benthamscience.net

Mohammad Khan

Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Syed Ehtaishamul Haque

Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Suhel Parvez

Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard

Email: info@benthamscience.net

Umar Jahangir

Department of Amraaz-e-Jild wa Tazeeniyat, School of Unani Medical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Mohammad Amir

Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Suruchi Khanna

Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard

Email: info@benthamscience.net

Mohammad Shaquiquzzaman

Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard

Author for correspondence.
Email: info@benthamscience.net

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