Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Coronavirus disease 2019 outbreak in Beijing's Xinfadi Market, China: a modeling study to inform future resurgence response.

BACKGROUND: A local coronavirus disease 2019 (COVID-19) case confirmed on June 11, 2020 triggered an outbreak in Beijing, China after 56 consecutive days without a newly confirmed case. Non-pharmaceutical interventions (NPIs) were used to contain the source in Xinfadi (XFD) market. To rapidly control the outbreak, both traditional and newly introduced NPIs including large-scale management of high-risk populations and expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR-based screening in the general population were conducted in Beijing. We aimed to assess the effectiveness of the response to the COVID-19 outbreak in Beijing's XFD market and inform future response efforts of resurgence across regions. METHODS: A modified susceptible-exposed-infectious-recovered (SEIR) model was developed and applied to evaluate a range of different scenarios from the public health perspective. Two outcomes were measured: magnitude of transmission (i.e., number of cases in the outbreak) and endpoint of transmission (i.e., date of containment). The outcomes of scenario evaluations were presented relative to the reality case (i.e., 368 cases in 34 days) with 95% Confidence Interval (CI). RESULTS: Our results indicated that a 3 to 14 day delay in the identification of XFD as the infection source and initiation of NPIs would have caused a 3 to 28-fold increase in total case number (31-77 day delay in containment). A failure to implement the quarantine scheme employed in the XFD outbreak for defined key population would have caused a fivefold greater number of cases (73 day delay in containment). Similarly, failure to implement the quarantine plan executed in the XFD outbreak for close contacts would have caused twofold greater transmission (44 day delay in containment). Finally, failure to implement expanded nucleic acid screening in the general population would have yielded 1.6-fold greater transmission and a 32 day delay to containment. CONCLUSIONS: This study informs new evidence that in form the selection of NPI to use as countermeasures in response to a COVID-19 outbreak and optimal timing of their implementation. The evidence provided by this study should inform responses to future outbreaks of COVID-19 and future infectious disease outbreak preparedness efforts in China and elsewhere.

Duplicated zebrafish co-orthologs of parathyroid hormone-related peptide (PTHrP, Pthlh) play different roles in craniofacial skeletogenesis.

In mammals, parathyroid hormone-related peptide (PTHrP, alias PTH-like hormone (Pthlh)) acts as a paracrine hormone that regulates the patterning of cartilage, bone, teeth, pancreas, and thymus. Beyond mammals, however, little is known about the molecular genetic mechanisms by which Pthlh regulates early development. To evaluate conserved pathways of craniofacial skeletogenesis, we isolated two Pthlh co-orthologs from the zebrafish (Danio rerio) and investigated their structural, phylogenetic, and syntenic relationships, expression, and function. Results showed that pthlh duplicates originated in the teleost genome duplication. Zebrafish pthlha and pthlhb were maternally expressed and showed overlapping and distinct zygotic expression patterns during skeletal development that mirrored mammalian expression domains. To explore the regulation of duplicated pthlh genes, we studied their expression patterns in mutants and found that both sox9a and sox9b are upstream of pthlha in arch and fin bud cartilages, but only sox9b is upstream of pthlha in the pancreas. Morpholino antisense knockdown showed that pthlha regulates both sox9a and sox9b in the pharyngeal arches but not in the brain or otic vesicles and that pthlhb does not regulate either sox9 gene, which is likely related to its highly degraded nuclear localization signal. Knockdown of pthlha but not pthlhb caused runx2b overexpression in craniofacial cartilages and premature bone mineralization. We conclude that in normal cartilage development, sox9 upregulates pthlh, which downregulates runx2, and that the duplicated nature of all three of these genes in zebrafish creates a network of regulation by different co-orthologs in different tissues.