Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia.

Protein arginine methyltransferase 3 (PRMT3) plays an important role in gene regulation and a variety of cellular functions, thus, being a long sought-after therapeutic target for human cancers. Although a few PRMT3 inhibitors are developed to prevent the catalytic activity of PRMT3, there is little success in removing the cellular levels of PRMT3-deposited ω-NG,NG-asymmetric dimethylarginine (ADMA) with small molecules. Moreover, the non-enzymatic functions of PRMT3 remain required to be clarified. Here, the development of a first-in-class MDM2-based PRMT3-targeted Proteolysis Targeting Chimeras (PROTACs) 11 that selectively reduced both PRMT3 protein and ADMA is reported. Importantly, 11 inhibited acute leukemia cell growth and is more effective than PRMT3 inhibitor SGC707. Mechanism study shows that 11 induced global gene expression changes, including the activation of intrinsic apoptosis and endoplasmic reticulum stress signaling pathways, and the downregulation of E2F, MYC, oxidative phosphorylation pathways. Significantly, the combination of 11 and glycolysis inhibitor 2-DG has a notable synergistic antiproliferative effect by further reducing ATP production and inducing intrinsic apoptosis, thus further highlighting the potential therapeutic value of targeted PRMT3 degradation. These data clearly demonstrated that degrader 11 is a powerful chemical tool for investigating PRMT3 protein functions.

Association of maternal body mass index and gestational weight gain rate with cardiometabolic traits in childhood: A prospective cohort study.

BACKGROUND AND AIMS: Evidence on the association of maternal obesity with offspring cardiometabolic health is limited, particularly for the Asian population. We aimed to examine the associations of maternal body mass index (BMI) in early pregnancy and gestational weight gain (GWG) rate in mid- and late-pregnancy with childhood cardiometabolic traits. METHODS AND RESULTS: We used data of 1452 mother-child pairs from a population-based prospective cohort study in China. Maternal BMI in early pregnancy and GWG rate in mid- and late-pregnancy were calculated. Childhood cardiometabolic traits were assessed at aged 4-7 years, including BMI, BMI-z, systolic blood pressure (SBP), diastolic blood pressure, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, total cholesterol, triglycerides, fasting glucose, and C-reactive protein. Each 1 kg/m2 increase in maternal BMI in early pregnancy was associated with 0.46% (95% confidence interval, 0.19%-0.72%) higher children BMI, 0.05 (0.02-0.08) higher BMI-z, 0.41% (0.22%-0.59%) higher waist circumference, and 0.24% (0.03%-0.46%) higher SBP. Each 1 kg/week higher GWG rate in mid- and late-pregnancy was associated with higher children SBP (4.58% [1.46%-7.71%]), triglycerides (18.28% [3.13%-33.44%]), and fasting glucose (5.83% [2.64%-9.02%]) and lower BMI-z (-0.45 [-0.82 to -0.08]). Additional adjustment for offspring BMI attenuated the associations for maternal BMI but not for GWG rate. CONCLUSIONS: The increase in maternal BMI and GWG are associated with adverse cardiometabolic profiles in childhood. The association between maternal BMI and childhood cardiometabolic traits is likely mediated using the offspring BMI.

Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

Design, Synthesis, and Biological Evaluation of 2,4-Diaminopyrimidine Derivatives as Potent CDK7 Inhibitors.

Developing selective CDK7 inhibitors has emerged as a promising approach for cancer treatment owing to the critical role of CDK7 in cancer progression. Starting from BTX-A51, a CK1α inhibitor that also targets CDK7 and CDK9, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as potent CDK7 inhibitors. The representative compound, 22, displayed significant enzymatic inhibitory activity and demonstrated a remarkable selectivity profile against a panel of kinases, including seven CDK subtypes. Modeling studies and molecular dynamics simulations revealed that the sulfone group of 22 significantly enhanced the binding affinity, while the acetyl group contributed to the increased selectivity of CDK7 against CDK9. Compound 22 effectively inhibited the phosphorylation of RNA polymerase II and CDK2 and resulted in G1/S phase cell cycle arrest and apoptosis in MV4-11 cells. It appears to be a promising lead compound for the development of a CDK7 inhibitor for cancer therapy.

LncRNA HOXA-AS3 promotes cell proliferation and invasion via targeting miR-218-5p/FOXP1 axis in osteosarcoma.

Osteosarcoma is an aggressive form of bone cancer and affects the health in children and adolescents. Although conventional treatment improves the osteosarcoma survival, some patients have metastasis and drug resistance, leading to a worse prognosis. Therefore, it is necessary to explore the molecular mechanism of osteosarcoma occurrence and progression, which could discover the novel treatment for osteosarcoma. Long noncoding RNAs (lncRNAs) have been reported to regulate osteosarcoma occurrence and malignant progression. LncRNA HOXA-AS3 facilitates the tumorigenesis and progression in a variety of human cancers. However, the underlying mechanism of lncRNA HOXA-AS3-induced oncogenesis is poorly determined in osteosarcoma. To address this point, we utilized several cellular biological strategies and molecular approaches to explore the biological functions and mechanisms of lncRNA HOXA-AS3 in osteosarcoma cells. We found that lncRNA HOXA-AS3 facilitates cell proliferation and invasion via targeting miR-218-5p/FOXP1 axis in osteosarcoma. In conclusion, lncRNA HOXA-AS3 could be a promising target for osteosarcoma treatment.

Discovery of a Highly Potent, Selective and Efficacious USP7 Degrader for the Treatment of Acute Lymphoblastic Leukemia.

USP7 is an attractive therapeutic target for cancers, especially for acute lymphoblastic leukemia (ALL) with wild-type p53. Herein, we report the discovery of XM-U-14 as a highly potent, selective and efficacious USP7 proteolysis-targeting chimera degrader. XM-U-14 achieves DC50 values of 0.74 nM and Dmax of 93% in inducing USP7 degradation in RS4;11 cell lines, and also significantly inhibits ALL cell growth. XM-U-14 even at 5 mg/kg dosed daily effectively inhibits RS4;11 tumor growth with 64.7% tumor regressions and causes no signs of toxicity in mice. XM-U-14 is a promising USP7 degrader for further optimization for ALL treatment.

GPR34 senses demyelination to promote neuroinflammation and pathologies.

Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies, but the mechanism is poorly understood. Here, we showed that lysophosphatidylserine (LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Thus, our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation, and suggest it as a potential therapeutic target for demyelination-associated diseases.

Highly exposed metal atomic active sites in Al2O3/CoNC: Modify reaction pathways by coupling oxygen species.

The catalytic oxidation of formaldehyde (HCHO) at ambient temperature is a highly efficient, cost-effective and environmentally friendly approach for formaldehyde removal. Reactive oxygen (O*) and reactive hydroxyl groups (OH*) are the main active species in the catalytic oxidation reaction of HCHO. Therefore, it is crucial to design catalysts that can simultaneously enhance the surface concentrations of O* and OH*, thereby improving their overall catalytic performance. The present study aimed to design an Al2O3/CoNC catalyst featuring layered carbon nitride coupled with metal oxides possessing domain-limited cobalt (Co) metal active sites, to efficiently remove HCHO (≈100 %, 100 ppm, RH=50 %, GSHV=20,000 mL/(g h)) and ensure stability (more than 90 % formaldehyde removal within 450 h) at ambient temperature. The characterization revealed that the interaction between Al2O3-supported metal and CoNC resulted in enhanced confinement of Co, leading to a higher abundance of edge structures exposing more active sites. Additionally, the presence of highly dispersed Co-NX active sites and increased oxygen vacancies effectively facilitated the adsorption and activation processes of HCHO and O2, as well as the adsorption and desorption dynamics of intermediates during the reaction. These factors collectively contributed to an improved catalytic activity. The results of in situ infrared spectroscopy revealed that the catalyst improved the adsorption and activation of O2 and H2O, leading to the rapid generation of substantial amounts of O* and OH*. This synergistic interaction between Al2O3 and CoNC plays a crucial role in the sustained production of O* and OH*, promoting efficient of intermediate decomposition, and ensuring excellent catalytic activity and stability for HCHO.

Discovery of Preclinical Candidate AD1058 as a Highly Potent, Selective, and Brain-Penetrant ATR Inhibitor for the Treatment of Advanced Malignancies.

The ataxia telangiectasia-mutated and Rad3-related protein (ATR) plays a crucial role in regulating the cellular DNA-damage response (DDR), making it a promising target for antitumor drug development through synthetic lethality. In this study, we present the discovery and detailed characterization of AD1058, a highly potent and selective ATR inhibitor, with good preclinical pharmacokinetic profiles. AD1058 exhibits superior efficacy in inhibiting cell proliferation, disrupting the cell cycle, and inducing apoptosis compared to AZD6738. AD1058 displays potent antitumor effects as a single agent or in combination with clinically approved tumor therapies such as PARP inhibitors, ionizing radiotherapy, or chemotherapy in vivo. Considering its enhanced ability to permeate the blood-brain barrier, AD1058 is a promising clinical candidate for the treatment of brain metastases and leptomeningeal metastases in solid tumors. Additionally, among reported ATR inhibitors, AD1058 features the shortest synthesis route and the highest efficiency to date.

Health-promotion interventions targeting multiple behaviors: A meta-analytic review of general and behavior-specific processes of change.

Although health-promotion interventions that recommend changes across multiple behavioral domains are a newer alternative to single-behavior interventions, their general efficacy and their mechanisms of change have not been fully ascertained. This comprehensive meta-analysis (6,878 effect sizes from 803 independent samples from 364 research reports, N = 186,729 participants) examined the association between the number of behavioral recommendations in multiple-behavior interventions and behavioral and clinical change across eight domains (i.e., diet, smoking, exercise, HIV [Human Immunodeficiency Virus] prevention, HIV testing, HIV treatment, alcohol use, and substance use). Results showed a positive, linear effect of the number of behavioral recommendations associated with behavioral and clinical change across all domains, although approximately 87% of the samples included between 0 and 4 behavioral recommendations. This linear relation was mediated by improvements in the psychological well-being of intervention recipients and, in several domains (i.e., HIV, alcohol use, and drug use), suggested behavioral cuing. However, changes in information, motivation, and behavioral skills did not mediate the impact of the number of recommendations on behavioral and clinical change. The implications of these findings for theory and future intervention design are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Effects of Breastfeeding on Childhood Behavioral and Emotional Development: A Prospective Cohort Study in China.

BACKGROUND: Breastfeeding could improve a child's health early on, but its long-term effects on childhood behavioral and emotional development remain inconclusive. We aimed to estimate the associations of feeding practice with childhood behavioral and emotional development. METHODS: In this population-based birth cohort study, data on feeding patterns for the first 6 mo of life, the duration of breastfeeding, and children's emotional and behavioral outcomes were prospectively collected from 2489 mother-child dyads. Feeding patterns for the first 6 mo included exclusive breastfeeding (EBF) and non-exclusive breastfeeding (non-EBF, including mixed feeding or formula feeding), and the duration of breastfeeding (EBF or mixed feeding) was categorized into ≤6 mo, 7-12 mo, 13-18 mo, and >18 mo. Externalizing problems and internalizing problems were assessed with the Child Behavior Checklist (CBCL) and operationalized according to recommended clinical cutoffs, corresponding to T scores ≥64. Multivariable linear regression and logistic regression were used to evaluate the association of feeding practice with CBCL outcomes. RESULTS: The median (interquartile range) age of children at the outcome measurement was 32.0 (17.0) mo. Compared with non-EBF for the first 6 mo, EBF was associated with a lower T score of internalizing problems [adjusted mean difference (aMD): -1.31; 95% confidence interval (95% CI): -2.53, -0.10], and it was marginally associated with T scores of externalizing problems (aMD: -0.88; 95% CI: -1.92, 0.15). When dichotomized, EBF versus non-EBF was associated with a lower risk of externalizing problems (aOR: 0.54, 95% CI: 0.34, 0.87), and it was marginally associated with internalizing problems (aOR: 0.75, 95% CI: 0.54, 1.06). Regarding the duration of breastfeeding, breastfeeding for 13-18 mo versus ≤6 mo was associated with lower T scores of internalizing problems (aMD: -2.50; 95% CI: -4.43, -0.56) and externalizing problems (aMD: -2.75; 95% CI: -4.40, -1.10), and breastfeeding for >18 mo versus ≤6 mo was associated with lower T scores of externalizing problems (aMD: -1.88; 95% CI: -3.68, -0.08). When dichotomized, breastfeeding for periods of 7-12 mo, 13-18 mo, and >18 mo was associated with lower risks of externalizing problems [aOR (95% CI): 0.96 (0.92, 0.99), 0.94 (0.91, 0.98), 0.96 (0.92, 0.99), respectively]. CONCLUSIONS: Exclusive breastfeeding for the first 6 mo and a longer duration of breastfeeding, exclusively or partially, are beneficial for childhood behavioral and emotional development.

Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors.

BRD9 is a pivotal epigenetic factor involved in cancers and inflammatory diseases. Still, the limited selectivity and poor phenotypic activity of targeted agents make it an atypically undruggable target. PROTAC offers an alternative strategy for overcoming the issue. In this study, we explored diverse E3 ligase ligands for the contribution of BRD9 PROTAC degradation. Through molecular docking, binding affinity analysis, and structure-activity relationship study, we identified a highly potent PROTAC E5, with excellent BRD9 degradation (DC50 = 16 pM) and antiproliferation in MV4-11 cells (IC50 = 0.27 nM) and OCI-LY10 cells (IC50 = 1.04 nM). E5 can selectively degrade BRD9 and induce cell cycle arrest and apoptosis. Moreover, the therapeutic efficacy of E5 was confirmed in xenograft tumor models, accompanied by further RNA-seq analysis. Therefore, these results may pave the way and provide the reference for the discovery and investigation of highly effective PROTAC degraders.

Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents a highly aggressive and heterogeneous malignancy. Currently, effective therapies for TNBC are very limited and remain a significant unmet clinical need. Targeting the transcription-regulating cyclin-dependent kinase 9 (CDK9) has emerged as a promising avenue for therapeutic treatment of TNBC. Herein, we report the design, synthesis, optimization, and evaluation of a new series of aminopyrazolotriazine compounds as orally bioavailable, potent, and CDK9/2 selectivity-improved inhibitors, enabling efficacious inhibition of TNBC cell growth, as well as notable antitumor effect in TNBC models. The compound C35 demonstrated low-nanomolar potency with substantially improved CDK9/2 selectivity, downregulated the CDK9-downstream targets (e.g., MCL-1), and induced apoptosis in TNBC cell lines. Moreover, with the desired oral bioavailability, oral administration of C35 could significantly suppress the tumor progression in two TNBC mouse models. This study demonstrates that target transcriptional regulation is an effective strategy and holds promising potential as a targeted therapy for the treatment of TNBC.

Two-sample Mendelian randomization studies revealed a causal relationship between insulin use and osteoporosis: An observational study.

OBJECTIVE: To investigate causal associations between diabetes, insulin treatment and osteoporosis using LDSC analysis with a 2-way Mendelian randomization study. METHODS: LDSC analysis was used to estimate the likelihood-scale heritability of the genome-wide association study used with genetic correlation between the 2 genome-wide association study used. Then a 2-sample Mendelian randomization study was performed using 3 methods including inverse variance weighted, MR Egger, and weighted median. RESULTS: The genetic correlation between diabetes, insulin treatment (h2_Z = 3.70, P = 2.16e-4), osteoporosis (h2_Z = 4.93, h2_p = 8.13e-7) and genes was significant. There was a significant genetic correlation (rg = 0.122, P = 0.0211). There was a causal association between diabetes, insulin treatment and osteoporosis [P = 0.003754, OR (95%CI) = 0.998876 (0.998116-0.999636)], while no causal association existed between osteoporosis and insulin use (P = 0.998116-0.999636) causal association existed (P = 0.333244). CONCLUSION: There was a strong genetic correlation between diabetes, insulin treatment and osteoporosis, a causal association between diabetes, insulin treatment and osteoporosis, and no causal association between osteoporosis and diabetes, insulin treatment.

Synthesis, Fluorescence, and Bioactivity of Novel Isatin Derivatives.

The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.

Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression.

High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.

Association of the triglyceride-glucose index and its related parameters with frailty.

BACKGROUND: Frailty is a dynamic geriatric condition. Limited studies have examined the association of the triglyceride-glucose (TyG) index and its related indicators [TyG index, triglyceride glucose-waist to height ratio (TyG-WHtR), triglyceride glucose-waist circumference (TyG-WC), and triglyceride glucose-body mass index (TyG-BMI)] with frailty, and the potential links among them remain unclear. On the basis of data from the National Health and Nutrition Examination Survey (NHANES), this study investigated the potential relationships of the TyG index and its related indices with frailty. METHODS: This research included 7,965 participants from NHANES 2003-2018. The relationship of the TyG index and its related indices with frailty was investigated with binary logistic regression analyses, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curve. Potential influences were further investigated through stratified analyses and interaction tests. RESULTS: The prevalence of frailty in the participants of this study was 25.59%, with a average frailty index of 0.16 (0.00). In the three regression analysis models, the continuous TyG index and its associated indices were positively associated with frailty. In addition, quartiles of TyG, TyG-WC, TyG-WHtR, and TyG-BMI were significantly associated with increased frailty prevalence in the fully adjusted models (TyG Q4 vs. Q1, OR = 1.58, 95% CI: 1.19, 2.09, P = 0.002; TyG-WC Q4 vs. Q1, OR = 2.40, 95% CI: 1.90, 3.04, P < 0.001; TyG-WHtR Q4 vs. Q1, OR = 2.26, 95% CI: 1.82, 2.81, P < 0.001; TyG- BMI Q4 vs. Q1, OR = 2.16, 95% CI: 1.76, 2.64, P < 0.001). According to RCS analysis, TyG, TyG-WC, TyG-WHtR, and TyG-BMI were linearly and positively associated with frailty. ROC curves revealed that TyG-WHtR (AUC: 0.654) had greater diagnostic value for frailty than TyG (AUC: 0.604), TyG-BMI (AUC: 0.621), and TyG-WC (AUC: 0.629). All of the stratified analyses and interaction tests showed similar results. CONCLUSIONS: Elevated TyG and its associaed indices are associated with an increased prevalence of frailty. Reasonable control of blood glucose and blood lipids, and avoidance of obesity, may aid in reducing the occurrence of frailty in middle-aged and older adults.

The association of maternal gestational weight gain with cardiometabolic risk factors in offspring: a systematic review and meta-analysis.

CONTEXT: Gestational weight gain (GWG) is known to be a risk factor for offspring obesity, a precursor of cardiometabolic diseases. Accumulating studies have investigated the association of GWG with offspring cardiometabolic risk factors (CRFs), leading to inconsistent results. OBJECTIVE: This study synthesized available data from cohort studies to examine the effects of GWG on offspring CRFs. DATA SOURCE: Four electronic databases, including PubMed, Web of Science, Scopus, and Embase, were searched through May 2023. DATA EXTRACTION: Cohort studies evaluating the association between GWG and CRFs (fat mass [FM], body fat percentage [BF%], waist circumference [WC], systolic blood pressure [SBP] and diastolic blood pressure, high-density-lipoprotein cholesterol [HDL-C] and low-density-lipoprotein cholesterol, triglyceride [TG], total cholesterol, fasting blood glucose, and fasting insulin levels) were included. Regression coefficients, means or mean differences with 95% confidence intervals [CIs], or standard deviations were extracted. DATA ANALYSIS: Thirty-three cohort studies were included in the meta-analysis. Higher GWG (per increase of 1 kg) was associated with greater offspring FM (0.041 kg; 95% CI, 0.016 to 0.067), BF% (0.145%; 95% CI, 0.116 to 0.174), WC (0.154 cm; 95% CI, 0.036 to 0.272), SBP (0.040 mmHg; 95% CI, 0.010 to 0.070), and TG (0.004 mmol/L; 95% CI, 0.001 to 0.007), and with lower HDL-C (-0.002 mmol/L; 95% CI, -0.004 to 0.000). Consistently, excessive GWG was associated with higher offspring FM, BF%, WC, and insulin, and inadequate GWG was associated with lower BF%, low-density lipoprotein cholesterol, total cholesterol, and TG, compared with adequate GWG. Most associations went non-significant or attenuated with adjustment for offspring body mass index or FM. CONCLUSIONS: Higher maternal GWG is associated with increased offspring adiposity, SBP, TG, and insulin and decreased HDL-C in offspring, warranting a need to control GWG and to screen for cardiometabolic abnormalities of offspring born to mothers with excessive GWG. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023412098.

Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during oncogenesis. Despite the potential of Pin1 as a drug target, its successful targeting has proved to be challenging. We speculate that only blocking the enzymatic function of Pin1 with inhibitors may not be sufficient to lead to a total loss-of-function. Here, we report the discovery of P1D-34, a first-in-class and potent PROTAC degrader of Pin1, which induced Pin1 degradation with a DC50 value of 177 nM and exhibited potent degradation-dependent anti-proliferative activities in a panel of acute myeloid leukemia (AML) cell lines. In contrast, Pin1 inhibitor Sulfopin did not show activity. More significantly, P1D-34 could sensitize Bcl-2 inhibitor ABT-199 in Bcl-2 inhibitor-resistant AML cells, highlighting the potential therapeutic value of targeted Pin1 degradation for Bcl-2 inhibitor-resistant AML treatment. Further mechanism study revealed that P1D-34 led to the up-regulation of ROS pathway and down-regulation of UPR pathway to induce cell DNA damage and apoptosis. Notably, we further demonstrated that treatment with the combination formula of glucose metabolism inhibitor 2-DG and P1D-34 led to a notable synergistic anti-proliferative effect, further expanding its applicability. These data clearly reveal the practicality and importance of PROTAC as a preliminary tool compound suitable for assessment of Pin1-dependent pharmacology and a promising strategy for AML treatment.

Discovery of 5-trifluoromethyl-2-aminopyrimidine derivatives as potent dual inhibitors of FLT3 and CHK1.

Here, we discover an FLT3/CHK1 dual inhibitor (30) that exhibits excellent kinase potency and antiproliferative activity against MV4-11 cells. Simultaneously, 30 possesses high selectivity over c-Kit enzyme and low hERG inhibitory ability. Compound 30, meanwhile, overcomes varied resistance in BaF3 cell lines carrying FLT3-TKD and FLT3-ITD mutations. Moreover, 30 demonstrates favorable oral PK properties and kinase selectivity. These conclusions support that compound 30 may be a promising potential FLT3/CHK1 dual agent for further development.