Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Circulatory metastin/kisspeptin-1 in polycystic ovary syndrome: a systematic review and meta-analysis with diagnostic test accuracy.

RESEARCH QUESTION: A close association between Kisspeptin-1 (KISS-1) and reproductive physiology has been reported, but the results on circulatory KISS-1 are ambiguous in patients with polycystic ovary syndrome (PCOS). A systematic review and meta-analysis were conducted to evaluate the association between KISS-1 and PCOS, and to test its diagnostic test accuracy (DTA) through DTA meta-analysis. DESIGN: Relevant studies were identified by searching PubMed and other databases in addition to manual searching of cross-references. Random-effects model was used to obtain standardized mean differences (SMD), pooled correlation coefficients and summary of DTA. Meta-regression and sub-group analyses were conducted to explore heterogeneity. The presence of publication bias was tested using funnel plot analysis. RESULTS: This meta-analysis finally included 12 studies. Compared with controls, women with PCOS showed significantly increased circulatory KISS-1 levels (SMD = 0.47; P = 0.002). Meta-analysis of correlations showed positive associations between KISS-1 and anti-Müllerian hormone (AMH) (P = 0.03), testosterone (P < 0.001) and dehydroepiandrosterone (P = 0.004). The pooled diagnostic odds ratio and area under curve were 13.71 and 0.835, respectively. A one-study leave-out sensitivity analysis indicated that no single study had a significant influence on the overall outcome, suggesting the robustness of this meta-analysis. CONCLUSIONS: This meta-analysis showed significantly increased KISS-1 level in PCOS, and its association with AMH reflects its role in reproductive physiology. In our DTA meta-analysis, KISS-1 showed good accuracy for PCOS detection. Further large-scale studies are required to establish its validity.

Circulating Angiopoietin-like 8 protein (ANGPTL8/Betatrophin) in patients with polycystic ovary syndrome: a systematic review and multi effect size meta-analysis.

The association between circulating betatrophin levels and polycystic ovary syndrome (PCOS) is controversial and the studies in the literature are inconsistent. The aim of our study was to systematically review and meta-analyze all available literature comparing circulating betatrophin levels between human PCOS patients and controls. Relevant studies were retrieved by online database and manual searching. A total of 11 studies were included in this meta-analysis. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. Meta-analysis of correlations was performed for the associations of betatrophin with anthropometric, lipid and hormonal covariates in PCOS patients. The results indicated that the betatrophin levels were significantly elevated in PCOS patients as compared to non-PCOS controls (SMD = 0.73, 95% CI = 0.22-1.24, Z = 2.83, p = .005). A one-study leave-out sensitivity analysis indicated that no single study had a significant influence on the overall outcome, suggesting the robustness of this meta-analysis. Our sub-group analysis indicated that this increase in betatrophin concentrations was regardless of normo-weight or obese body mass index (BMI) and insulin resistance might have an important role. There were significant positive correlations of betatrophin with age, free androgen index and free-testosterone in PCOS patients. In summary, regardless of BMI, the circulatory betatrophin levels are elevated in PCOS patients compared to controls. PCOS patients with higher insulin resistance had substantially higher circulating betatrophin concentrations.