In 2017, CDER (Food and Drug Administration, USA) approved 46 new drugs, out of which 12 (26%) were anti-cancer drugs [1]. Here, we review the mechanism of action of various approved anti-cancer drugs (Table 1).

Kinase Inhibitors: The various kinase inhibitors approved included: acalabrutinib, abemaciclib, copanlisib dihydrochloride, neratinib, brigatinib and ribociclib.

Acalabrutinib is an inhibitor of Bruton tyrosine kinase (BTK) [Figure 1]. BTK, also known as agammaglobulinemia tyrosine kinase (ATK) or B-cell progenitor kinase (BPK), is a non-receptor tyrosine kinase that was initially identified as the defective protein in human X-linked agammaglobulinemia (XLA) [2]. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways that is expressed in B-cells, myeloid cells, mast cells, and platelets. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Chronic activation of the BCR pathway is involved in the proliferation and cell survival of various B-cell malignancies. In steady state conditions, BTK is predominantly cytosolic, unphosphorylated and catalytically inactive. BTK activation is a complex process and a critical step in this process requires translocation of BTK to the plasma membrane [3].

Abemaciclib and Ribociclib have activity against cyclin‐dependent kinase 4 (CDK4) and CDK6 [Figure 2]. The mammalian cell cycle involves sequential activation of related heterodimeric protein kinases, including a catalytic subunit, the cyclin-dependent kinase (CDK), and a regulatory subunit, the cyclin. CDK4 and CDK6 are activated by the D-type cyclins and implicated in regulating the early phases of the cell cycle, especially during exit from quiescence. CDK4/6-cyclin D heterodimeric kinases promote re-entry into the cycle by initiating phosphorylation of the retinoblastoma protein family, Rb, p107, and p130. Rb phosphorylation results in the liberation of transcription factors, e.g., members of the E2F family, which are bound to the hypophosphorylated Rb proteins in non-proliferation cells. These transcription factors are responsible for directing the expression of genes essential for advancing cells through the S phase of the cell cycle. The expression of cyclins, such as Cyclin-D1, determines, in part, the extent to which their CDK counterparts are activated. Cyclin expression is regulated by gene transcription downstream of cellular signaling pathways, such as those activated by mitogenic stimuli. In addition, regulation of the cell cycles includes cellular inhibitors of CDKs and cyclin-CDK complexes, such as p27/Kip1 or p16/INK4a, and other signaling molecules. There is some redundancy of the activities among the different types and pairings of cyclin-CDKs, such that loss or inhibition of one or more of these complexes in a certain cell type may be compensated for by another cyclin-CDK or through some other compensatory mechanism and cell division may not be completely blocked. The expression pattern of cyclins, CDKs and cyclin-CDK inhibitors in various cell types may determine whether a CDK has a redundant or non-redundant role in a specific cell type [4]. In estrogen receptor‐positive (ER+) breast cancer, ER activation promotes cyclin D1 transcription and activation of CDK4/6‐Rb pathway, leading to uncontrolled cell proliferation.

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) [Figure 3]. PI3K is a lipid kinase involved in activation of the PI3K/3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT pathways. PI3K also modulates guanosine triphosphate exchange factor (GEPFs) activity through generation of phosphoinositol-3-phosphate (PIP3). The PI3K-α and PI3K-δ isoforms are expressed in malignant B cells [5].

Neratinib is a new molecular entity and an orally available small molecule kinase inhibitor [Figure 4]. It irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The HER signaling pathways are normally involved in regulation of cell growth and survival as well as adhesion, migration, differentiation, and other cellular responses. There are four members of the family, including EGFR/HER1, HER2, HER3, and HER4 (also called erbB-1, erbB-2, erbB-3, and erbB-4, respectively) [6].

Brigatinib is a tyrosine kinase inhibitor that has activity against multiple kinases including anaplastic lymphoma kinase (ALK), ROS1, insulin-like growth factor receptor-1 (IGF-1R), and FLT-3 as well as EGFR.

Midostaurin is a small molecule inhibitor of fms-like tyrosine kinase-3 (FLT3) and tyrosine kinase KIT (KIT) [Figure 5]. FLT3 (FMS-like tyrosine kinase 3) belongs to a type III receptor tyrosine kinase together with KIT, FMS and PDGF-receptor. FLT3 expresses on the surface of normal hematopoietic stem/progenitor cells. FLT3 ligand (FL) is expressed by bone marrow stroma cells, and FL-FLT3 interaction plays an important role in the survival, proliferation and differentiation of normal hematopoietic stem/progenitor cells. In addition, FLT3 expresses in most AML (acute myeloid leukemia) and ALL (acute lymphocytic leukemia) cells, and FL-stimulation enhances proliferation and reduces apoptosis of leukemia cells [7].

Isocitrate dehydrogenase 2 (IDH2) inhibitor: Enasidenib is an isocitrate dehydrogenase 2 (IDH2) inhibitor. The IDH enzymes catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), producing nicotinamide adenine dinucleotide phosphate (NADPH) in the process via the citric acid cycle. Some mutant forms of IDH enzymes catalyze the reduction of α-KG to an oncometabolite known as 2-hydroxyglutarate (2-HG), while consuming NADPH [8].

Poly (ADPribose) polymerase (PARP) inhibitor: Niraparib is a new molecular entity and inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2 [Figure 6]. PARP is a family of proteins involved in DNA repair. Inhibition of PARP enzymatic activity can result in DNA damage, apoptosis and cell death. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b). The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others [9].

Antibody-Drug Conjugate: Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) consisting of a humanized CD22-directed IgG4 monoclonal antibody (inotuzumab, G544) and a semi-synthetic derivative of the cytotoxic natural product γ-calicheamicin (N-acetyl-γ-calicheamicin dimethylhydrazide or N-Ac-γ-calicheamicin DMH), with a small molecule-to-antibody ratio of approximately 6:1 [Figure 7]. Antibody-drug conjugates (ADCs) consist of cytotoxic drugs covalently linked to monoclonal antibodies directed to antigens differentially overexpressed in tumor cells. These loaded antibodies are expected to selectively deliver lethal cargoes to tumor cells and provide sustained clinical benefit to pre-selected cancer patients while, at the same time, minimizing systemic toxicity. The combination of MAb and cytotoxin lends itself to synergism. MAbs may act as target-selective anti-cancer agents by number of different mechanisms: complement-dependent cytolysis (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody dependent phagocytosis, induction of apoptosis, depletion of circulating tumor cells, and interference with cellular signaling associated with proliferative activity [10].

Programmed death-ligand 1 (PD-L1) blocking antibody: Approved PD-L1 blocking antibodies included durvalumab and avelumab.

Durvalumab and Avelumab are human IgG1 monoclonal antibodies that bind to human programmed death ligand 1 (PD-L1), thereby inhibiting the interaction of PD-L1 with PD-1 and B7-1 receptors [Figure 8]. PD-L1 is a member of the B7 family of ligands that regulate the activation of T cells through binding to PD1 and CD80 receptors. PD-L1 is expressed on cells of the immune system and on many human tumors at high frequency. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 on activated T cells and delivers inhibitory signal resulting in inhibition of T-cell activation; thereby preventing killing of target tumor cells and immune elimination of tumors. The expression of PD-L1 is associated with poor prognosis for patient survival. In nonclinical studies, it was reported that blocking PD-L1 interaction with its receptors releases inhibition of the immune response, resulting in enhanced immune surveillance and response, including immune-mediated anti-tumor activity [11]. An additional mechanism of action proposed for avelumab is antibody dependent cell mediated cytotoxicity (ADCC) which is thought to occur as a result of the engagement of fragment crystalline receptors on cytotoxic natural killer cells and macrophages.