Small-molecule Smac mimetics are being developed as a novel class of anticancer drugs. Recent studies have shown that Smac mimetics target cellular inhibitor of apoptosis protein (cIAP)-1/2 for degradation and induce tumor necrosis factor-A (TNFA)-dependent apoptosis in tumor cells. In this study, we have investigated the mechanism of action and therapeutic potential of two different types of novel Smac mimetics, monovalent SM-122 and bivalent SM-164. Our data showed that removal of cIAP-1/2 by Smac mimetics or small interfering RNA is not sufficient for robust TNFA-dependent apoptosis induction, and X-linked inhibitor of apoptosis protein (XIAP) plays a critical role in inhibiting apoptosis induction. Although SM-164 is modestly more effective than SM-122 in induction of cIAP-1/2 degradation, SM-164 is 1,000 times more potent than SM-122 as an inducer of apoptosis in tumor cells, which is attributed to its much higher potency in binding to and antagonizing XIAP. SM-164 induces rapid cIAP-1 degradation and strong apoptosis in the MDA-MB-231 xenograft tumor tissues and achieves tumor regression, but has no toxicity in normal mouse tissues. Our study provides further insights into the mechanism of action for Smac mimetics and regulation of apoptosis by inhibitor of apoptosis proteins. Furthermore, our data provide evidence that SM-164 is a promising new anticancer drug for further evaluation and development. [Cancer Res 2008;68(22):9384-93]

To confirm the relationship between sex and the progression of Coronavirus , and its potential mechanism, among severe patients. For this retrospective study, we included 168 consecutive severe patients with pathogen-confirmed COVID-19 who were hospitalized between January 16th and February 4th, 2020, at Tongji Hospital in Wuhan, China. Clinical characteristics, laboratory parameters, and outcomes were compared and analyzed between males and females. In the present study, we analyzed 168 severe patients with COVID-19, including 86 males and 82 females, and 48 patients (28.6%) were diagnosed as critically ill. Of 86 male patients, 12.8% (11/86) died and 75.6% (65/86) were discharged; of 82 female patients, 7.3% (6/82) died and 86.6% (71/82) were discharged. Eleven laboratory parameters showed significant differences between male and female patients, and six of them were higher during the whole clinical course in patients who died than in patients who were discharged. In adjusted logistic regression analysis, males with comorbidities presented a higher risk of being critically ill than males without comorbidities (OR = 3.824, 95% CI = 1.279-11.435). However, this association attenuated to null in female patients (OR = 2.992, 95% CI = 0.937-9.558). A similar sex-specific trend was observed in the relation between age and critically ill conditions. We highlighted sexspecific differences in clinical characteristics and prognosis. Male patients appeared to be more susceptible to age and comorbidities. Sex is an important biological variable that should be considered in the prevention and treatment of COVID-19. PLOS PATHOGENSPLOS Pathogens | https://doi.

We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.

XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains. We report the design, synthesis and characterization of a non-peptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC 50 value of 1.39 nM, being 300 and 7000-times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultra-potent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in leukemia cancer cells, while having a minimal toxicity to normal human primary cells at 10,000 nM. The potency of bivalent SM-164 in binding, functional and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.

BACKGROUND/OBJECTIVES Previous studies have reported that older patients may experience worse outcome(s) after infection with severe acute respiratory syndrome coronavirus‐2 than younger individuals. This study aimed to identify potential risk factors for mortality in older patients with coronavirus disease 2019 (COVID‐19) on admission, which may help identify those with poor prognosis at an early stage. DESIGN Retrospective case‐control. SETTING Fever ward of Sino‐French New City Branch of Tongji Hospital, Wuhan, China. PARTICIPANTS Patients aged 60 years or older with COVID‐19 (n = 244) were included, of whom 123 were discharged and 121 died in hospital. MEASUREMENTS Data retrieved from electronic medical records regarding symptoms, signs, and laboratory findings on admission, and final outcomes of all older patients with COVID‐19, were retrospectively reviewed. Univariate and multivariate logistic regression analyses were used to explore risk factors for death. RESULTS Univariate analysis revealed that several clinical characteristics and laboratory variables were significantly different (ie, P < .05) between discharged and deceased patients. Multivariable logistic regression analysis revealed that lymphocyte (LYM) count (odds ratio [OR] = 0.009; 95% confidence interval [CI] = 0.001‐0.138; P = .001) and older age (OR = 1.122; 95% CI = 1.007‐1.249; P = .037) were independently associated with hospital mortality. White blood cell count was also an important risk factor (P = .052). The area under the receiver operating characteristic curve in the logistic regression model was 0.913. Risk factors for in‐hospital death were similar between older men and women. CONCLUSION Older age and lower LYM count on admission were associated with death in hospitalized COVID‐19 patients. Stringent monitoring and early intervention are needed to reduce mortality in these patients. J Am Geriatr Soc 68:E19–E23, 2020.

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The synthesis from l-quebrachitol of a series of 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation of Akt and downstream substrates without affecting activation of the upstream kinase, PDK-1, or other kinases downstream of ras such as MAPK in H157 and H1703 lung cancer cells that have high levels of constitutively active Akt. The 2-hydroxyl in these compounds was deleted or alkylated with the intent to preclude metabolic degradation of these compounds by PI-specific phospholipase C (PI-PLC). PI analogues with phosphate linkers are more effective than those with carbonate linkers. Specific inhibition of Akt by these compounds validates ligand design targeted to the PH domains of crucial signaling proteins, thus providing a unique class of possible cancer therapeutics.

Background: Cells are exposed to elevated levels of CO 2 (hypercapnia) in many diseases. Results: Hypercapnia decreased cell proliferation, which was prevented with ␣-ketoglutarate, IDH2 overexpression, and microRNA-183 inhibition. Conclusion: Hypercapnia causes mitochondrial dysfunction by up-regulation of microRNA-183, which decreases the levels of IDH2. Significance: Hypercapnia causes mitochondrial dysfunction, which is relevant for patients with lung diseases.