An Updated Review of Smac Mimetics, LCL161, Birinapant, and GDC-0152 in Cancer Treatment

Abstract

Inhibitor of apoptosis proteins (IAPs) are suggested as therapeutic targets for cancer treatment. Smac/DIABLO is a natural IAP antagonist in cells; therefore, Smac mimetics have been developed for cancer treatment in the past decade. In this article, we review the anti-cancer potency and novel molecular targets of LCL161, birinapant, and GDC-0152. Preclinical studies demonstrated that Smac mimetics not only induce apoptosis but also arrest cell cycle, induce necroptosis, and induce immune storm in vitro and in vivo. The safety and tolerance of Smac mimetics are evaluated in phase 1 and phase 2 clinical trials. In addition, the combination of Smac mimetics and chemotherapeutic compounds was reported to improve anti-cancer effects. Interestingly, the novel anti-cancer molecular mechanism of action of Smac mimetics was reported in recent studies, suggesting that many unknown functions of Smac mimetics still need to be revealed. Exploring these currently unknown signaling pathways is important to provide hints for the modification and combination therapy of further compounds.

Inhibition of BIRC2 Sensitizes α7-HPV-Related Cervical Squamous Cell Carcinoma to Chemotherapy

“…BIRC2 is a member of the antiapoptosis gene family, inhibiting apoptosis by interfering with the activation of caspases and SMAC mimetic compounds LCL161, birinapant (TL32711), and GDC-0152 were tested as anticancer agents in clinical trials [23].…”

“…In one study, several chemotherapeutic agents (e.g., paclitaxel, cisplatin and topotecan) were used against cervical SCC [24]. Clinical trials on patients with advanced solid tumors involving cotreatment with LCL161 and paclitaxel, as well as cotreatments with other chemotherapeutic agents, are ongoing [23,25]. Notably, studies have reported that a combination of LCL161 with cisplatin, vincristine, or immune checkpoint inhibitors produced the highest antitumor activity in cancer cells [26][27][28].…”

“…Notably, studies have reported that a combination of LCL161 with cisplatin, vincristine, or immune checkpoint inhibitors produced the highest antitumor activity in cancer cells [26][27][28]. The combination of LCL161 with topotecan was tested for ovarian cancer [23]; however, this combination has yet to be tested for cervical cancer. Immunotherapies (particularly those involving immune checkpoint inhibitors) have demonstrated great potential in cervical cancer treatment, and multiple phase III trials are underway [29].…”

Special Issue on “Anticancer Drugs Activity and Underlying Mechanisms”

“…A review study from Chang et al [35] reported the recent results determining the role of second mitochondria-derived activators of apoptosis (smac) mimetics, birinapant, LCL161, and GDC-0152, in cancer treatment. These molecules, which have entered in phase 1 and 2 clinical trials, are able to induce the non-canonical NF-kB signaling pathway and downregulate the protein expression inhibitor level of apoptosis proteins (IAPs), leading to cells death by apoptosis, even though other mechanisms are still under investigation.…”

Clinically relevant SMAC mimetics do not enhance human T cell proliferation or cytokine production

“…In preclinical in vivo animal models, SMAC mimetics showed encouraging results, particularly when used in tandem with chemotherapy drugs to further sensitize cancer cells to chemotherapy 6,[8][9][10][11][12][13][14] . However, in clinical trials, SMAC mimetics have yet to show efficacy as a monotherapy or to increase efficacy in combination with chemotherapy or immunotherapy 15 .…”