**5.3 X-linked inhibitor of apoptosis protein (XIAP) inhibitors**

Although IAPs control plethora of signaling pathways, they were initially thought to be responsible for caspase inhibition by acting as negative regulators of apoptosis [36, 37]. Many small molecules have been designed to target the IAP proteins and one such category of an molecules is Smac mimetics (SMs). A recently developed XIAP inhibitor BMT-062789 displays remarkable anticancer activity against a panel of lymphoma cell lines. BMT-062789 is a heterodimeric mimetic of the second mitochondrial activator of caspases (SMAC) [47]. This molecule inhibits both the caspase 9 and caspase 3/7 binding domains of XIAP [48]. When used in combination with etoposide, BMT-062789 induces apoptosis in rituximab resistant cell line models Raji 4RH and RL 4RH. ASTX660 is another orally bioavailable, non-peptidomimetic antagonist of both XIAP and cellular IAP1 (cIAP1), with potential antineoplastic and pro-apoptotic activities. ASTX660 selectively binds to and inhibits the activity of XIAP and cIAP1 [49].

#### **5.4 Caspase activators in cancer therapy**

Caspases constitutes a group of cytosolic aspartate-specific cysteine proteases that participate in the initiation and execution of apoptosis Pharmacological activation of caspases using small molecule activators is an effective therapeutic

*Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy DOI: http://dx.doi.org/10.5772/intechopen.97536*


#### **Table 3.**

*Pharmacological characteristics of some Mcl-1 inhibitors.*


#### **Table 4.**

*Caspase activators.*

strategy to kill cancer cells and can potentially help to reverse drug resistance. The most important cysteine protease in the caspase cascade is caspase 3 [50]. In a normal cell, capase-3 is typically in anactive form by an intramolecular electrostatic interaction favored by triplet of aspartic acid residues (also known as safety-catch). Although, there are indication that cell death can proceed in the absence of caspases, activation caspase family members is critical for execution of cell death in apoptotic cells. Several drugs for activating caspases exist (**Table 4**). An important caspase-inducing agent is apoptin, which is a proline-rich protein capable of inducing apoptosis in cancer cells in a selective manner. This protein is obtained from chicken anemia virus that causes tumor-specific apoptosis without interfering with normal cells. As such, apoptin is considered as a highly tumor-specific therapeutic agent [51, 52]. This drug is still in preclinical testing.

## **6. Conclusion**

Due to its role in tissue homeostasis and cancer pathogenesis, apoptosis has received tremendous attention as a target for therapeutic intervention of cancer. Thus targeting apoptotic signaling networks is an important therapeutic strategy for cancer therapy. Many drugs have been developed that modulate different components of apoptotic signaling. However, many tumors ultimately develop

drug resistance against these drugs. Therefore there is a need to develop novel therapeutic agents and new treatment strategies that can reverse the drug-resistant phenotype of tumors and render these tumors sensitive towards therapeutic regimens. A limited number of FDA-approved drugs exist that directly target apoptotic pathways. Many of these drugs target the Bcl-2 family member such as Bcl-2 itself and Mcl-1. Caspase 3 activators are also being tested in preclinical settings. Other therapeutic strategies involve the use of drugs that activate the extrinsic pathway of apoptosis or tumor suppressor pathways or modulate tumor microenvironment. However, it is interesting to conclude that apoptosis can be induced in cancer cells by activating both the intrinsic and extrinsic pathways of apoptosis. However there is a need to identify therapeutic targets that are unique to cancer cells so that their modulation may not affect the normal surrounding cells. Thus, while targeting apoptotic signaling networks, there is a need to ensure tumor-specific apoptosis without inducing apoptosis in normal cells. We are hopeful that, in future, a better understanding of apoptotic signaling may lead to the development of novel anticancer drugs that could target different components of apoptotic signaling selectively and specifically. However, the lack of precise relationship between level of proteins involved in apoptosis and the clinical outcome poses a big challenge in the development of novel therapeutic agents and as such warrants in-depth understanding of apoptotic signaling networks.
