Chemical Reviews pubs.acs.
org/CR Review
Figure 1. Therapeutic targeting of the hallmarks of cancer. Reproduced with permission from ref 47. Copyright 2011 Elsevier.
indications, with the first approval being gemtuzumab agents such as bromodomain inhibitors, histone acetyl
ozogamicin (Mylotarge) for CD-33 positive acute myeloid transferase inhibitors, histone deacetylase inhibitors, protein
leukemia (AML) in 2001.23 Further breakthrough treatments methyltransferase inhibitors, and histone methylation inhib-
include the FDA approval of the drug bevacimzumab itors which target DNA methylation.32 Another recent
(Avastin), which is an antiangiogenic that targets tumors by development is the use of chimeric antigen receptor modified
blocking the growth of blood vessels as opposed to the direct R cell (CAR-T) therapy, which genetically modifies the
targeting of tumor cells. First approved in 2004 for patients patient’s own T cells to target specific cancers. In 2013 a
with colorectal cancer (CRC), it is now available for treatment clinical trial showed complete remissions in two children
of multiple indications including lung, ovarian, and kidney suffering from acute lymphoblastic leukemia (ALL).33
cancers.24 The past decade has seen a range of additional targeted
In the past two decades there has been an explosion of small molecules against different proteins and cancer
interest in approaches to the boost the body’s immune system indications which work through a variety of mechanisms of
to enable it to target cancers, referred to as immuno-oncology action including reversible and covalent inhibitors.34 A major
(IO). In 2010, the drug ipilimumab (Yervoy), a monoclonal focus of current drug discovery efforts is to broaden the
antibody which blocks the protein CTLA-4 thereby stimulating modality of targeted agents to include mRNA based
T-cells, was reported to improve the survival of patients with therapeutics,35 cyclic peptides,36 bifunctional degraders
advanced melanoma.25 In 2014, two “immune checkpoint commonly referred to as proteolysis targeting chimeras
inhibitors” were approved for the treatment of melanoma. (PROTACs),37 bicyclic drug conjugates,38 and other agents
Pembrolizumab (Keytruda) and nivolumab (Opdivo) block including oligonucleotide therapeutics (ASOs)39 and oncolytic
the PD-1 pathway which prevents the body’s immune system viruses.40 This review will focus on the small molecule
from targeting cancer cells.26−28 These agents more recently approaches throughout the various case studies but acknowl-
have been approved in multiple indications including edge key examples of other modalities.
NSCLC.29 One review published in September 2019 reported 1.2. Emergence of Personalized Medicine in Cancer
that there were 5166 active clinical trials in the IO space, with Treatment
31 FDA approvals in the past 2 years.30 The ability of drug discovery scientists to target cancers has
A review from the same year also highlighted the potential become increasingly sophisticated, as genetic information has
additional role of epigenetic factors, which is the study of become more freely available driven by the reduced cost of
heritable changes in gene expression that do not involve exome and whole genome sequencing.41 In addition,
changes to the underlying DNA sequence.31 These include proteomic approaches such as immunohistochemistry have
C https://dx.doi.org/10.1021/acs.chemrev.0c00383
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