Optimization of mTOR Inhibitors Using Property-Based Drug Design and Free-Wilson Analysis for Improved In Vivo Efficacy.

The mTOR kinase regulates a variety of critical cellular processes and has become a target for the treatment of various cancers. Using a combination of property-based drug design and Free-Wilson analysis, we further optimized a series of selective mTOR inhibitors based on the (S)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one scaffold. Our efforts resulted in 14c, which showed similar in vivo efficacy compared to previous lead 1 at 1/15 the dose, a result of its improved drug-like properties.

Persistence Pays Off: Live Birth after Uterus Transplant, Overcoming Recurrent Pregnancy Loss with Cerclage Placement.

Recipients of uterus transplantation have unique factors that may increase their risk of cervical insufficiency. This report describes a uterus transplant recipient with cervical insufficiency resulting in two second-trimester miscarriages. After McDonald cerclages (one that failed), she underwent an interval transabdominal cerclage and delivered a healthy term child in her third pregnancy. The longitudinal information of this case provides observations from which we can propose testable hypotheses that address venous outflow and inflammation. This case also suggests that there could be a role for prophylactic cerclage placement at the time of transplantation.

Neonatal Outcomes after Uterus Transplantation: Dallas Uterus Transplant Study.

OBJECTIVE: Limited data are available on the outcome of infants born after uterus transplantation. Our aim was to describe the hospital course and laboratory findings in the first 2 months of life of the 12 infants born in the Dallas UtErus Transplant Study (DUETS). STUDY DESIGN: Based on the trial protocol, information about infants was collected in a prospective fashion, including infant demographics, hospital course, and laboratory values. RESULTS: Twelve infants were delivered, all by cesarean section, from 11 mothers who had undergone uterus transplantation (one mother had two pregnancies and delivered two babies). All pregnancies were singleton. The mothers received immunosuppressive therapy, and one had a rejection episode that was detected during pregnancy. The rejection episode resolved after steroid treatment. The infants had a median gestational age of 366/7 weeks (range: 306/7-380/7 weeks) and median birth weight of 2,920 g (range: 1,770-3,470 g). The lowest Apgar's score at 5 minutes was 8. All infants were appropriate size for gestational age. Two infants presented with bandemia but negative blood cultures. At 2 months of age, all infants achieved the developmental and behavioral milestones outlined by the American Academy of Pediatrics. CONCLUSION: The 12 infants born from mothers with uterus transplants had a neonatal course that reflected the gestational age at delivery. No baby was born with an identified malformation or organ dysfunction. Longer follow-up and a larger number of infants are needed to confirm these observations. KEY POINTS: · Normal fetal development after uterus transplantation.. · No baby was born with malformations or showed any organ dysfunction.. · At 2 months, all infants achieved appropriate developmental and behavioral milestones..

Clinical pregnancy rates and experience with in vitro fertilization after uterus transplantation: Dallas Uterus Transplant Study.

BACKGROUND: The clinical pregnancy rates among patients with uterus transplantation have been reported by only a limited number of centers, and those centers have not used preimplantation genetic testing for aneuploidy in their protocol. OBJECTIVE: This study examined clinical pregnancy rates among women with absolute uterine-factor infertility undergoing in vitro fertilization using good-quality, expanded-blastocyst-stage, euploid embryos after uterus transplantation. STUDY DESIGN: This cohort observational study involved 20 women who underwent uterus transplantation over 3 years. Notably, 14 of these patients had successful transplants and were followed prospectively for a median of 14.1 months (range, 11-34.8 months). In vitro fertilization was performed before subjects underwent uterus transplantation, and good-quality expanded-blastocyst-stage euploid embryos were obtained and frozen for future embryo transfer. Interventions consisted of in vitro fertilization, preimplantation genetic testing for aneuploidy, uterus transplantation, and frozen embryo transfer. RESULTS: All 14 subjects with successful transplants underwent single embryo transfer of a warmed, good-quality, euploid, expanded blastocyst and had at least 1 documented clinical pregnancy within the uterus. In 71.4%, the first embryo transfer resulted in clinical pregnancy. The median time from successful uterus transplantation to first embryo transfer was 4.5 months; from successful uterus transplantation to first clinical pregnancy, 7.3 months; and from successful uterus transplantation to first live birth, 14.1 months. A total of 13 live births have occurred in 12 subjects. CONCLUSION: Women with absolute uterine-factor infertility who have surgically successful uterus transplantation and in vitro fertilization using preimplantation genetic testing for aneuploidy can achieve high clinical pregnancy rates. We have reduced the time interval from uterus transplantation to embryo transfer by at least 50% and the interval from uterus transplantation to clinical pregnancy by >6 months compared with previous studies. We believe our approach may shorten the time from transplant to clinical pregnancy and therefore decrease patient exposure to immunosuppressant therapies.

Twelve Live Births After Uterus Transplantation in the Dallas UtErus Transplant Study.

OBJECTIVE: To describe aggregated pregnancy outcomes after uterus transplantation from a single, experienced center. METHODS: This prospective study reports on live births among 20 women who received a uterus transplant from 2016 to 2019 at Baylor University Medical Center at Dallas. These live births occurred between November 2017 and September 2020. The main measures were live birth, maternal complications, and fetal and newborn outcomes. RESULTS: There were six graft failures (four surgical complications and two with poor perfusion postoperatively). Of the 14 technically successful transplants, at least one live birth occurred in 11 patients. Thus far, the live birth rate per attempted transplant is 55%, and the live-birth rate per technically successful transplant is 79%. Ten uteri were from nondirected living donors and one uterus was from a deceased donor. In vitro fertilization was performed to achieve pregnancy. Ten recipients delivered one neonate, and one recipient delivered two neonates. One organ rejection episode was detected during pregnancy and was resolved with steroids. The median birth weight was 2,890 g (range 1,770-3,140 g [median 68th percentile]). Maternal weight gain was higher than Institute of Medicine recommendations. Maternal medical complications were observed in five recipients (elevated creatinine level, gestational diabetes, gestational hypertension [n=2], and preeclampsia). In five recipients, maternal medical or obstetric complications led to an unplanned preterm delivery (elevated creatinine level, preeclampsia; preterm labor [n=3]). The median gestational age at delivery was 36 6/7 weeks (range 30 6/7-38 weeks). All neonates were liveborn, with Apgar scores of 8 or higher at 5 minutes. CONCLUSION: Over the first 3 years, our program experienced a live-birth rate per attempted transplant of 55% and a live-birth rate per technically successful transplant of 79%. In our experience, uterus transplantation resulted in a third-trimester live birth in all cases in which pregnancies reached 20 weeks of gestation. Maternal medical and obstetric complications can occur; however, these were manageable by applying principles of generally accepted obstetric practice. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02656550.

Rational discovery of a highly novel and selective mTOR inhibitor.

Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases.

Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1).

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.

Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.

Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers.

Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy.

The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy.

TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G(2)-M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC(50) values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC(50) >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers.