SM-164 / Ascenta - LARVOL DELTA

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

Taraxasterol alleviates osteoporosis by targeting PI3K/AKT/PPARγ signaling axis to suppress necroptosis and reverse osteogenic-adipogenic differentiation imbalance in BMSCs. (PubMed, Phytomedicine) - "Our study reveals for the first time that TAX restores osteogenic-adipogenic equilibrium in OP-BMSCs and promotes bone regeneration through PI3K/AKT/PPARγ activation and mitochondrial protection-mediated suppression of necroptosis. These results position TAX as a promising therapeutic candidate for osteoporosis."

Journal • Oncology • Osteoporosis • Rheumatology • PPARG • TNFA

SPOP mediates apoptosis and protects against necroptosis by regulating ubiquitination of RIPK1 and RIPK3. (PubMed, JCI Insight) - "Based on these findings, a combination therapy using the second mitochondria-derived activator of caspases (Smac) mimetic SM164 and sunitinib was developed, demonstrating a more pronounced efficacy than sunitinib monotherapy, and this sensitizing effect was dependent on the expression level of RIPK1. These results suggest that the combination of Smac mimetics with tyrosine kinase inhibitors holds potential clinical value for tumors with dysregulated SPOP/RIPK1/RIPK3 signaling."

Journal • Breast Cancer • Clear Cell Carcinoma • Clear Cell Renal Cell Carcinoma • Hepatocellular Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • RIPK1 • SPOP • TNFA

Etoposide-loaded lipopolymer nanoparticles promote Smac minetic activity against inhibitor of apoptosis protein for glioblastoma treatment. (PubMed, Biomater Adv) - "Encapsulated BV6 and SM164, two bivalent second mitochondria-derived activator of caspase (Smac) mimetics, in etoposide (ETO)-lipopolymer nanoparticles (NPs) have been developed to deplete inhibitor of apoptosis proteins (IAP), impair DNA, and produce antagonistic effects on glioblastoma multiforme (GBM) in nude mice. Compared to untreated mice, the current ETO preparation carrying Smac mimetics reduced cellular IAP-1 expression to about 33 % and X-linked IAP expression to about 42 %, while enhanced about 3.8-fold caspase-3, indicating the effectiveness of the nanocarriers in accelerating apoptosis of GBM cells. Tf-WGA-CB-PVA-NPs can be promising to upgrade BV6 and SM164 activity by ETO in clinical trials for GBM management."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • XIAP

Polysaccharides from Cordyceps cicadae Ameliorate Reproductive Impairments in Male Mouse through the Hypothalamic-Pituitary-Testicular Axis. (PubMed, Mol Nutr Food Res) - "These results manifest that CCP-1 could serve as a natural promising reproductive system protective supplement for ameliorating CTX biotoxicity."

Journal • Preclinical • Diabetes • CASP3 • KIT • TNFA

Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy. (PubMed, Cancer Immunol Immunother) - "An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome."

Journal • Breast Cancer • Hematological Malignancies • Oncology • Solid Tumor • Targeted Protein Degradation • BIRC3 • MUC1 • TNFA

Birinapant selectively enhances immunotoxin-mediated killing of cancer cells conditional on the IAP protein levels within target cells. (PubMed, FASEB J) - "Of interest, two Smac mimetics, birinapant and SM164, exhibited this kind of differential enhancement. In tumor xenograft studies, combinations of immunotoxin and birinapant caused complete regressions in MDA-MB-468tumor-bearing mice but not in mice with A431 tumors. We propose that IAPs constitute a barrier to immunotoxin efficacy which can be overcome with combination treatments that include Smac mimetics."

Journal • Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Targeted Protein Degradation • Triple Negative Breast Cancer • TNFA

RIP3/MLKL regulates necroptosis via activating 4EBP1-eIF4E pathway. (PubMed, Zhong Nan Da Xue Xue Bao Yi Xue Ban) - "4EBP1-eIF4E pathway is activated in the RIP3/MLKL mediated-necroptosis."

Journal • EIF4E • EIF4EBP1 • MLKL • mTOR • TNFA

Ehrlichia Notch signaling induction promotes XIAP stability and inhibits apoptosis. (PubMed, Infect Immun) - "Furthermore, treatment with SM-164, a second mitochondrial activator of caspases (Smac/DIABLO) antagonist, resulted in decreased procaspase levels and increased caspase activation, induced apoptosis, and significantly decreased infection...Moreover, ectopic expression of TRP120 HECT Ub ligase catalytically defective mutant in HeLa cells decreased NICD and XIAP levels and increased caspase activation compared to HeLa cells with functional HECT Ub ligase catalytic activity (TRP120-WT). This investigation reveals a mechanism whereby E. chaffeensis modulates Notch signaling to stabilize XIAP and inhibit apoptosis."

Journal • Infectious Disease • Oncology • Targeted Protein Degradation • CASP3 • FBXW7 • NICD • XIAP

Apoptosis or Antiapoptosis? Interrupted Regulated Cell Death of Host Cells by Ascovirus Infection In Vitro. (PubMed, mBio) - "Four different chemicals were used to induce apoptosis at different stages of ascovirus infection: hydrogen peroxide (HO) and actinomycin D (ActD) had similar effects on the ascovirus-infected cells, whereas cMYC inhibitors and tumor necrosis factor alpha (TNF-α) plus SM-164 apoptosis inducers (T/S) had similar effects on infected cells. The RCD of insect cells is quite different from that of mammals, and studies on the former are many fewer than those on the latter, especially in the case of RCD in lepidopteran insects. Our results will lay a foundation for understanding the RCD of lepidopteran insects and its function in the process of insect virus infection."

Journal • Preclinical • Infectious Disease • Oncology • CASP6 • MYC • TNFA

IAPs antagonist SM164 ameliorates experimental MPO-ANCA-associated vasculitis via enhancing fatty acid oxidation in neutrophils. (PubMed, Rheumatology (Oxford)) - "Inhibition of IAPs with SM164 played a protective role in AAV through enhancing intracellular fatty acid oxidation in neutrophils."

Journal • Glomerulonephritis • Immunology • Inflammation • Lupus Nephritis • Nephrology • Renal Disease • Vasculitis • BIRC3 • MPO • XIAP

Lipopolysaccharide sensitizes the therapeutic response of breast cancer to IAP antagonist. (PubMed, Front Immunol) - "IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • MYD88 • TLR4

Enhanced activity of AZD5582 and SM-164 in rabies virus glycoprotein-lactoferrin-liposomes to downregulate inhibitors of apoptosis proteins in glioblastoma. (PubMed, Mater Sci Eng C Mater Biol Appl) - "Immunofluorescence and western-blot results revealed that AZD5582- and SM-164-encapsulated liposomes facilitated mutual curative intensity, effectively triggered apoptosis of U87 MG and HBCSCs, reduced the expression of cellular IAP 1 (cIAP1) and X-linked IAP (XIAP), and enhanced the expression of caspase-3. Hence, RGV-Lf-liposomes carrying AZD5582 and SM-164 can be promising formulations to activate apoptosis of U87 MG and HBCSCs, and this functionalized drug delivery system targeting cIAP and XIAP is a potential strategy to cure glioblastoma in clinical cancer management."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CASP3 • XIAP

Primary Cutaneous Desmoplastic Melanoma With Collagen Rosettes and Pseudoglandular Features. (PubMed, Am J Dermatopathol) - "Molecular analysis detected a mutation in the NF1 gene [c.4084C > T, p.(Arg1362Ter)], 2 different pathogenic mutations in TP53 [c.742C > T, p.(Arg248Trp), AF:12%, COSM1640831 and c.528C > G, p.(Cys176Trp), AF:12%, COSM11114], and a mutation in GNAS [c.601C > T, p.(Arg201Cys), AF: 9%, COSM123397]. To the best of our knowledge, this is the first case reporting collagen rosettes and pseudoglandular features in primary cutaneous DM."

Journal • Melanoma • Oncology • Solid Tumor • GNAS • NES • NF1 • NGF • SOX10 • TP53

Influence of Catecholamines (Epinephrine/Norepinephrine) on Biofilm Formation and Adhesion in Pathogenic and Probiotic Strains of Enterococcus faecalis. (PubMed, Front Microbiol) - "Four E. faecalis strains were included in this study: E. faecalis MMH594 and E. faecalis V583, pathogenic strains of clinical origin, E. faecalis Symbioflor 1 clone DSM 16431, a pharmaceutical probiotic, and E. faecalis OB15, a probiotic strain previously isolated from Tunisian rigouta (Baccouri et al., 2019). Future experiments will aim to confirm by in vivo studies the role of VicK as adrenergic sensor in E. faecalis probiotic and pathogen strains. This may help to develop new strategies of antagonism/competition in the gut or skin ecological niches, and to prevent the colonization by opportunistic pathogens."

Journal • Infectious Disease • Inflammatory Arthritis

Bacillus salitolerans sp. nov., a novel bacterium isolated from a salt mine in Xinjiang province, China. (PubMed) - "is proposed. The type strain is KC1(T) (=JCM 19760(T) = CGMCC 1.12810(T))."

Journal • Biosimilar

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice. (PubMed, Sci Rep) - "SM-164 did not kill adriamycin-resistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IL4

SM‑164 enhances the antitumor activity of adriamycin in human U2‑OS cells via downregulation of X‑linked inhibitor of apoptosis protein. (PubMed, Mol Med Rep) - "Compared with ADM + SM‑164 group, XIAP silencing with ADM + SM‑164 treatment further reduced cell viability, promoted apoptosis, increased caspase‑7, ‑9 and ‑3, and PARP expression; however the expression of survivin and cIAP‑1 were reduced. Combined ADM and SM‑164 treatment may be considered as potential therapeutic agent in the treatment of osteosarcoma, possibly via reductions XIAP expression."

Journal • PARP Biomarker

Lottiidibacillus patelloidae gen. nov., sp. nov., isolated from the intestinal tract of a marine limpet and reclassification of Bacillus taeanensis as Maribacillus taeanensis gen. nov., comb. nov. (PubMed, Antonie Van Leeuwenhoek) - "Based on phylogenetic analyses, B. taeanensis should be transferred to a new genus, named Maribacillus, as Maribacillus taeanensis comb. nov., with type strain BH030017 (= KCTC 3918 = DSM 16466)."

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Probiotic Potential and Safety Evaluation of Enterococcus faecalis OB14 and OB15, Isolated From Traditional Tunisian Testouri Cheese and Rigouta, Using Physiological and Genomic Analysis. (PubMed, Front Microbiol) - "...These new isolates were evaluated for probiotic properties, compared to E. faecalis Symbioflor 1 clone DSM 16431, as reference...Susceptibility to ampicillin, vancomycin, gentamicin and erythromycin has been tested using the broth microdilutions method...Hierarchical cluster analysis by MALDI TOF-MS biotyper showed that E. faecalis OB15 was closely related to the E. faecalis Symbioflor 1 probiotic strain than to OB14, and this has been confirmed by WGS using the average nucleotide identity (ANI) and Genome-to-Genome Hybridization similarity methods. According to these results, E. faecalis OB15 seems to be reliable for future development as probiotic, in food or feed industry."

Clinical • Journal

Kocuria tytonis sp. nov., isolated from the uropygial gland of an American barn owl (Tyto furcata). (PubMed, Int J Syst Evol Microbiol) - "...Phylogenetic analyses based on the 16S rRNA gene identified Kocuria rhizophila DSM 11926 (99.6 % similarity), Kocuria salsicia DSM 24776 (98.7 %), Kocuria varians DSM 20033 (98.3 %) and Kocuria marina DSM 16420 (98.3 %) as the most closely related species...is proposed. The type strain is 442 (=DSM 104130=LMG 29944)."

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