Current Directions and Trends of Cancer Chemotherapy: An Overview of the Recently Approved Small-Molecules Anticancer Drugs in the Past Decade An Overview of the Drugs

Background: The everlasting challenge to develop more potent, more selective and less toxic chemotherapeutic antitumor drugs constitutes a substantial weapon to defeat the continuous multidrug resistance characteristics of many cancers. Therefore, the need for the discovery and development of unprecedented antineoplastics drugs still exists. Results: In this mini review a survey of the novel targets and trends in cancer chemotherapy has been investigated to explore the potential therapeutic lines and treatment protocols. 70 novel small-molecule antineoplastic were studied and categorized according to their mode of action, medicinal use, year of FDA-approval as well as chemical structures. The vast majority of these recently approved drugs over the past decade are kinase inhibitors while the hormone antagonists represent the minority of these novel drugs. The two years of 2018 and 2020 represent the years of the highest approval numbers of small-molecules anticancer drugs with 10 approved drugs, while the year of 2016 is the one with the least number of just 2 newly approved drugs. Conclusion: In this study, a quick and yet comprehensive survey has been conducted to explore the major targets and trends in the last decade with respect to small-molecule anticancer drugs that have been recently FDA-approved. A new approach of classification of these drugs based on their detailed mechanism of action was demonstrated.


Introduction
Cancer as a broad expression of various malignancies remains as a global health concern as it accounts for more than 10 million annual mortalities throughout the past few years representing about 14.6% of deaths globally. Therefore, Cancer as a major health problem and a life-threatening disease stands out as the based on the detailed mechanism of action could be investigated via exploring the main novel trends of the recently approved anticancer drugs. This minireview includes only the FDA approved small molecules anticancer drugs from 2011 to 2020. Despite being apart from the scope of the current review, it is worthy to mention that the passing decade witnessed the dawn of cancer immunotherapy via the inhibition of the regulation of the adaptive immune response against malignancy. The prototype of this class Ipilimumab was approved in 2011 as an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), for the treatment of melanoma [3]. The focus of this review is substantially directed to small-molecules anticancer drugs since they constitute a major segment of all the approved small molecules in > 26% ratio and in > 17% of all approved drugs (with all categories that include biologicals and biopharmaceuticals), as represented in Table 1.

Alkylating agents
These agents directly interact with the DNA in the minor groove and methylate the DNA at guanine bases in the C-G rich region. Thus, they affect the transcription process and DNA repair mechanism [69]. Example of this class is Trabectedin (2015)

Histone-modifying enzymes inhibitors
Histone deacetylase (HDAC) enzyme regulates different DNA-linked processes via deacetylation of histone proteins to be accessible with other enzymes related to replication, transcription, repair, and chromatin remodeling. Inhibition of this enzyme results in growth inhibition and apoptosis induction [73]. Panobinostat (2015) is a HDAC inhibitor that is indicated for treating multiple myeloma in combination with other anticancer agents [74].
Belinostat (2014) is another HDAC inhibitor that is indicated for refractory peripheral T-cell lymphoma [75]. On the other hand, methyltransferase methylates the lysine and arginine residues in histone proteins, regulating the gene expression. Tazemetostat (2020) is a methyltransferase inhibitor that inhibits hypertrimethylation of histones and hence, preventing cancer cell dedifferentiation. It is indicated for treating epithelioid sarcoma [76,77].

Others
The FDA approved a combination of trifluridine and tipiracil Tipiracil is a thymidine phosphorylase inhibitor, that Prevents the degradation of the active trifluridine. This combination is indicated for colorectal cancer [78][79][80].
Consequently, the cells undergo cell cycle arrest and apoptotic cell death [97,98]. Finally, Carfilzomib (2012) is a proteasome inhibitor via inhibition of its chymotrypsin-like activity. It is indicated for treatment of refractory multiple myeloma [99].