ASN100 / X4 Pharma - LARVOL DELTA

Nuclear targeted Saccharomyces cerevisiae asparagine synthetases associate with the mitotic spindle regardless of their enzymatic activity. (PubMed, PLoS One) - "To find out if yeast asparagine synthetase can also (but hiddenly) have this feature, the coding sequences of green fluorescent protein (GFP) and nuclear localization signal (NLS) were introduced downstream of ASN1 and ASN2, encoding asparagine synthetases Asn1p and Asn2p, respectively, in the yeast genome having mCherrry coding sequence downstream of TUB1 encoding alpha-tubulin, a building block of the mitotic spindle...Furthermore, nocodazole treatment was used to depolymerize the mitotic spindle, resulting in lack of association between the enzyme and the mitotic spindle. Although yeast cell division undergoes closed mitosis, preventing the association of its asparagine synthetase with the mitotic spindle, however, by using yeast constructs with re-localized Asn1/2p have suggested the moonlighting role of asparagine synthetase in cell division of higher eukaryotes."

Journal • ASNS

Preventing lung pathology and mortality in rabbit Staphylococcus aureus pneumonia models with cytotoxin-neutralizing monoclonal IgGs penetrating the epithelial lining fluid. (PubMed, Sci Rep) - "Pharmacokinetic analysis of ASN100 in bronchoalveolar-lavage fluid from uninfected animals detected efficient penetration to lung epithelial lining fluid reaching peak levels between 24 and 48 hours post dosing that were comparable to the mAb concentration measured in serum. These data confirm that the ASN100 mAbs neutralize the powerful cytotoxins of S. aureus in the lung and prevent damage to the mucosal barrier and innate immune cells."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Results of a Phase 2, randomised, Double-Blind, Placebo-Controlled Study to Determine the Safety and Efficacy of a Single Dose of the Monoclonal Antibody Combination ASN100 for the Prevention of Staphylococcus aureus Pneumonia in Endotracheal Heavily colonised, Mechanically Ventilated Subjects (ECCMID 2019) - "The incidence of S. aureus pneumonia was far below the expected rate based on previous reports, such that a reduction by ASN100 could not be adequately demonstrated in a study of this size. The reduction in all bacterial pneumonias was not statistically significant. ASN100 was reasonably safe and well tolerated in an ICU population but the reasons for markedly shorter serum half-life compared to healthy volunteers remain unclear."

Clinical • P2 data • Hematological Disorders • Infectious Disease • Pneumonia • Respiratory Diseases • Thrombocytopenia

Molecular mechanism study of several inhibitors binding to BRD9 bromodomain based on molecular simulations. (PubMed, J Biomol Struct Dyn) - "Moreover, it is observed that BRD9 is anchored by the formation of a stable hydrogen bond between the carbonyl of the inhibitors and the residue Asn100 (at BC loop), and a strong π-π stacking interaction formed between the residue Tyr106 (at BC loop) and the inhibitors...The existence of dimethoxyphenyl structure and the aromatic ring merged to pyridinone scaffold are useful to enhance the BRD9 binding affinity. These findings should guide the rational design of more prospective inhibitors targeting BRD9."

Journal • Oncology

Saccharomyces cerevisiae ASN1 and ASN2 are asparagine synthetase paralogs that have diverged in their ability to polymerize in response to nutrient stress. (PubMed, Sci Rep) - "Using mutations that block enzyme activity but have differential effects on Asn1p polymerization, we have found that Asn1p polymers are unlikely to have acquired a moonlighting function. Together these results provide a novel system for understanding the regulation and evolution of metabolic enzyme polymerization."

Journal

Penetration of a Monoclonal Antibody Combination (ASN100) Targeting S. aureus Cytotoxins in Lung Epithelial Lining Fluid: A Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study in Healthy Volunteers. (PubMed, Antimicrob Agents Chemother) - "No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days post-dosing.The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100."

Clinical • Journal

Molecular mechanism of inhibitor bindings to bromodomain-containing protein 9 explored based on molecular dynamics simulations and calculations of binding free energies. (PubMed, SAR QSAR Environ Res) - "In addition, inhibitor-residue interactions were computed by using residue-based free-energy decomposition method and the results suggest that residue His42 produces the CH-H interactions, residues Asn100, Ile53 and Val49 produce the CH-[Formula: see text] interactions with three inhibitors and Tyr106, Phe45 and Phe44 generate the π-π interactions with inhibitors. Notably, the residue Asn140 forms hydrogen bonding interactions with three inhibitors. This research is expected to provide useful molecular basis and dynamics information at atomic levels for the design of potent inhibitors inhibiting the activity of BRD9."

Journal • Oncology

Insight into Selective Mechanism of class of I-BRD9 Inhibitors toward BRD9 Based on Molecular Dynamics Simulations. (PubMed, Chem Biol Drug Des) - "Besides, several key residues Phe44, Ile53, Asn100, Thr104 in BRD9 and Pro82, Lys91, Asn140, Asp144 in BRD4 that are located in the ZA-loop and BC-loop provide significant contributions to binding selectivity of inhibitors to BRD9 and BRD4. This study is expected to provide important theoretical guidance for rational designs of highly selective inhibitors targeting BRD9 and BRD4."

Journal

Prevention of S. Aureus Pneumonia Study in Mechanically Ventilated Subjects Who Are Heavily Colonized With S. Aureus. (clinicaltrials.gov) - P2; N=155; Terminated; Sponsor: Arsanis, Inc.; Completed ➔ Terminated; As a result of a pre-planned interim analysis for futility

Clinical • Trial termination

"Zoltan Magyarics (Austria) RCT of ASN100 monoclonal antibodies neutralising six S. aureus cytotoxins for prevention of pneumonia in colonised patients on ICU: did not reduce pneumonia in >100 patients. #eccmid2019" (@DJFMack)

Clinical