Eternity Bioscience (United States)

AC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100-600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% of patients, most commonly nausea (19%), fatigue (16%), and neutropenia (16%). All treatment-related adverse events were Grade 1/2, with no dose reductions/discontinuations; the maximum tolerated dose was not reached. Of 26 efficacy-evaluable patients, 4 (15%) achieved partial responses and CBR was 23%. In exploratory analysis of patients with ESR1 mutations, ORR and CBR were 40% and 45%, respectively. Median DOR and PFS were 6.5 and 3.6 months overall, and 6.5 and 7.4 months in ESR1-mutant patients. AC699 steady-state exposure increased approximately dose-proportionally between 100-400 mg, plateauing at 600 mg. AC699 demonstrated favorable safety, predictable PK, and encouraging antitumor activity, particularly in ESR1-mutant disease.

Nanotechnology is an innovative field focused on manipulating matter at the molecular and atomic scale, typically below 100 nanometers. It enables the design, creation, and application of systems with enhanced properties due to nanoscale precision. Molecular nanotechnology (MNT) integrates engineering with molecular chemistry and physics, offering substantial advancements in medicine, environmental cleanup, and other fields. Significant milestones include the invention of the Scanning Tunneling Microscope (STM) in 1981 and Eric Drexler's popularization of the field with his book "Engines of Creation." Nanotechnology has revolutionized medicine with improved drug delivery systems, diagnostic tools, and medical imaging. In environmental science, it has enabled advanced filtration systems and pollution control methods. Different types of nanoparticles, such as metal, semiconductor, polymeric, lipid, carbon-based, and magnetic nanoparticles, have unique properties and applications across various industries. Despite its benefits, nanotechnology raises health and environmental concerns, leading to the emergence of nanotoxicology and nanomedicine to study and mitigate hazards. The evolution of nanotechnology has significantly impacted healthcare, electronics, energy, and materials. Regulatory challenges and health concerns present obstacles to commercialization, requiring collaborative efforts and proactive risk management.

The present study determines the related substances in lansoprazole intermediate by using stability-indicating HPLC method. Lansoprazole intermediate is the critical raw material for synthesizing the drug substance, lansoprazole. The purity of the lansoprazole intermediate determines the quality of the lansoprazole drug substance with high yield in the synthetic process during the manufacturing. A novel, reversed-phase liquid chromatographic method was developed and validated to determine related substances in the lansoprazole intermediate. The symmetric peak shape was on a C18 stationary phase with the dimensions of 250 mm column length, 4.6 mm as internal diameter, and 5 microns particles with an economical and straightforward mass-compatible mobile phase combination of formic acid/triethylamine and acetonitrile delivered in gradient mode at a flow rate of 1.0 mL/min at 260 nm. The resolution between the lansoprazole intermediate and its impurities in the developed method was more than 2.0, indicating a significant separation. Regression analysis shows a correlation coefficient greater than 0.999 for lansoprazole intermediate and related substances. Lansoprazole Intermediate's detection and quantitation limits and impurities are 0.01% and 0.005%, respectively. This method indicates that the recovery at different levels is 90 to 110% accurate. The test solution was stable in the diluent for 48 hours. The results of forced degradation studies implied that the Lansoprazole Intermediate was sensitive to acid/base hydrolysis and oxidation conditions, and the mass balance was close to 99.5%. This study used the HPLC system Agilent Technologies 1200, a quaternary pump, an autosampler, and a diode array detector. The chromatographic output signal was monitored and processed by Empower software on an Intel Core i5 computer (Dell).

Stimulator of interferon genes (STING) activation induces type I interferons and pro-inflammatory cytokines which stimulate tumor antigen cross presentation and the adaptive immune responses against tumor. The first-generation of STING agonists, cyclic di-nucleotide (CDN), mimicked the endogenous STING ligand cyclic guanosine monophosphate adenosine monophosphate, and displayed limited clinical efficacy. Here we report the discovery of SHR1032, a novel small molecule non-CDN STING agonist. Compared to the clinical CDN STING agonist ADU-S100, SHR1032 has much higher activity in human cells with different STING haplotypes and robustly induces interferon β (IFNβ) production. When dosed intratumorally, SHR1032 induced strong anti-tumor effects in the MC38 murine syngeneic tumor model. Pharmacodynamic studies showed induction of IFNβ, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) in the tumors and, to a lower extent, in the plasma. More importantly, we found SHR1032 directly causes cell death in acute myeloid leukemia (AML) cells. In conclusion, our findings demonstrate that in addition to their established ability to boost anti-tumor immune responses, STING agonists can directly eradicate AML cells, and SHR1032 may present a new and promising therapeutic agent for cancer patients.

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060-73. ©2018 AACR.

Abstract Bruton's tyrosine kinase (Btk) is an essential component of the B-cell receptor (BCR) signaling pathways regulating survival, activation, proliferation, and differentiation of B lymphocytes. The first Btk inhibitor, Ibrutinib, has demonstrated a significant clinical efficacy in a variety of B-cell malignancies. Through structure-guided approach, we have discovered two series of novel and potent Btk inhibitors, represented by EBI-1266 and EBI-1367, respectively. Both of these compounds showed high potency in inhibiting Btk kinase activity and growth of a number of aggressive lymphoma cell lines driven by aberrant BCR signaling, with IC50 value within low nanomolar range. Mechanistic studies examining BCR signaling pathway in related B cell lymphoma cell lines revealed that both EBI-1266 and EBI-1367 potently inhibited Btk phosphorylation and downstream Erk phosphorylation, similar to Ibrutinib. Furthermore, each compound showed unique and significant superiority over Ibrutinib: EBI-1266 had a cleaner selectivity profile against a panel of kinases with a cysteine residue in the conserved catalytic domain, and EBI-1367 exhibited >10-fold higher in vivo exposure in multiple preclinical species. In a tumor xenograft mouse model where tumor growth is dependent on Btk activity, both EBI-1266 and EBI-1367 showed significant oral anti-tumor activities, with EBI-1367 being more efficacious than Ibrutinib, consistent with a higher exposure of EBI-1367 in both blood and tumor tissues. No evidence of overt toxicities was observed in rodents with prolonged oral administration for two weeks with doses at least 3-fold above a highly efficacious dose. In summary, the pharmacological profiles of EBI-1266 and EBI-1367 indicate that these compounds have a great potential to become the next generation of Btk inhibitors, offering advantages in pharmaceutical development, enhanced in vivo efficacy and reduced toxicities. We are currently performing IND-enabling studies aiming to initiate phase I clinical trials for these Btk inhibitors. Citation Format: Jiayin Zhang, Dong Liu, Ru Shen, Yinfa Yan, Liuqing Yang, Minsheng Zhang, Jun Feng, Beibei Fu, Jerry Hu, Biao Lu, Hong Wan, Lei Zhang, Weikang Tao, Lianshan Zhang, Jingsong Cao. Discovery and pharmacological characterization of the second generation of Btk inhibitors with improved target selectivity and enhanced in vivo efficacy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2599. doi:10.1158/1538-7445.AM2015-2599

The clinically beneficial effect of low frequency pulsed electromagnetic fields (ELF-PEMF) on bone healing has been described, but the exact mechanism of action remains unclear. A recent study suggests that there is a direct autocrine mitogenic effect of ELF-PEMF on angiogenesis. The hypothesis of this study is that ELF-PEMF also has an indirect effect on angiogenesis by manipulation of vascular endothelial growth factor (VEGF)-A-based paracrine intercellular communication with neighboring osteoblasts. Conditioned media experiments measured fetal rat calvarial cell (FRC) and human umbilical vein endothelial cell (HUVEC) proliferation using tritiated thymidine uptake. We demonstrate that ELF-PEMF (15 Hz, 1.8 mT, for 8 h) has an indirect effect on the proliferation rate of both endothelial cells and osteoblasts in vitro by altering paracrine mediators. Conditioned media from osteoblast cells stimulated with ELF-PEMF increased endothelial proliferation 54-fold, whereas media from endothelial cells stimulated with ELF-PEMF did not affect osteoblast proliferation. We examined the role of the pro-angiogenic mediator VEGF-A in the mitogenic effect of ELF-PEMF-stimulated osteoblast media on endothelial cells. The production of VEGF-A by FRC as measured by ELISA was not changed by exposure to PEMF, and blocking experiments demonstrated that the ELF-PEMF-induced osteoblast-derived endothelial mitogen observed in these studies was not VEGF-A, but some other soluble angiogenic mediator.

Drosophila innubila is a mushroom-feeding member of the quinaria group, found in the woodlands and forests of the 'sky islands' in Arizona and New Mexico and extending south into central Mexico. Here, we describe and characterize 30 polymorphic microsatellite loci from D. innubila collected in the Chiricahua Mountains in Arizona. The number of alleles ranged from three to 21, and observed heterozygosity ranged from 0.0513 to 0.9737. Six loci were putatively X-linked, six departed from Hardy-Weinberg equilibrium, seven had evidence of null alleles, and six showed evidence of linkage disequilibrium. These markers will be useful for examining population structure of D. innubila and its association with male-killing Wolbachia.