Discovery of Novel Fedratinib-Based HDAC/JAK/BRD4 Triple Inhibitors with Remarkable Antitumor Activity against Triple Negative Breast Cancer.

Multitarget HDAC inhibitors capable of simultaneously blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway hold great potential for the treatment of TNBC and other solid tumors. Herein, novel Fedratinib-based multitarget HDAC inhibitors were rationally designed, synthesized, and biologically evaluated, among which compound 25ap stood out as a potent HDAC/JAK/BRD4 triple inhibitor. Satisfyingly, compound 25ap led to concurrent inhibition of HDACs and the BRD4-LIFR-JAK1-STAT3 signaling pathway, which was validated by hyper-acetylation of histone and α-tubulin, hypo-phosphorylation of STAT3, downregulation of LIFR, MCL-1, and c-Myc in MDA-MB-231 cells. The multitarget effects of 25ap contributed to its robust antitumor response, including potent antiproliferative activity, remarkable apoptosis-inducing activity, and inhibition of colony formation. Notably, 25ap possessed an acceptable therapeutic window between normal and cancerous cells, desirable in vitro metabolic stability in mouse microsome, and sufficient in vivo exposure via intraperitoneal administration. Additionally, the in vivo antitumor potency of 25ap was demonstrated in an MDA-MB-231 xenograft model.

Discovery of neddylation E2s inhibitors with therapeutic activity.

Neddylation is the writing of monomers or polymers of neural precursor cells expressed developmentally down-regulated 8 (NEDD8) to substrate. For neddylation to occur, three enzymes are required: activators (E1), conjugators (E2), and ligators (E3). However, the central role is played by the ubiquitin-conjugating enzymes E2M (UBE2M) and E2F (UBE2F), which are part of the E2 enzyme family. Recent understanding of the structure and mechanism of these two proteins provides insight into their physiological effects on apoptosis, cell cycle arrest and genome stability. To treat cancer, it is therefore appealing to develop novel inhibitors against UBE2M or UBE2F interactions with either E1 or E3. In this evaluation, we summarized the existing understanding of E2 interaction with E1 and E3 and reviewed the prospective of using neddylation E2 as a pharmacological target for evolving new anti-cancer remedies.

Timely identification and successful treatment of acute fatty liver of pregnancy without obvious clinical symptoms: Case reports.

RATIONALE: Acute fatty liver of pregnancy (AFLP) is a rare and potentially fatal complication that occurs in the third trimester or early postpartum period. The diagnosis of AFLP is based on typical clinical and laboratory features and imaging examinations. PATIENT CONCERNS: Case 1: a 25-year-old pregnant woman was hospitalized for threatened preterm birth at gestation of 35weeks and 2 days gestation. Laboratory tests revealed liver dysfunction, coagulopathy, hypoglycemia, hypoproteinemia, leukocytosis, and elevated creatinine and uric acid levels. Case 2: a 28-year-old (nulliparous) became pregnant after in vitro fertilization-embryo transfer at 29 weeks and 1 days' gestation and came to the obstetric ward for vaginal bleeding. At 34 weeks and 1 day, laboratory investigations showed high serum creatinine, uric acid, liver dysfunction, coagulopathy, and hypoglycemia. DIAGNOSES: Two patients did not show obvious clinical symptoms, while the ultrasound findings confirmed a diagnosis of AFLP. INTERVENTIONS: Immediate delivery and comprehensive supportive treatment are the most important methods for the treatment of AFLP. OUTCOMES: The 2 patients and their babies were discharged from the hospital in a good condition. LESSONS: Special attention should be paid to mothers with AFLP after in vitro fertilization-embryo transfer. The clinical presentation of AFLP is variable, hence laboratory features and ultrasound examination may be important methods for screening for AFLP.