Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

The transverse momentum spectrum of weak gauge bosons at N 3 LL + NNLO.

We present accurate QCD predictions for the transverse momentum ( p ⊥ ) spectrum of electroweak gauge bosons at the LHC for 13 TeV collisions, based on a consistent combination of a NNLO calculation at large p ⊥ and N 3 LL resummation in the small p ⊥ limit. The inclusion of higher order corrections leads to substantial changes in the shape of the differential distributions, and the residual perturbative uncertainties are reduced to the few percent level across the whole transverse momentum spectrum. We examine the ratio of p ⊥ distributions in charged- and neutral-current Drell-Yan production, and study different prescriptions for the estimate of perturbative uncertainties that rely on different degrees of correlation between these processes. We observe an excellent stability of the ratios with respect to the perturbative order, indicating a strong correlation between the corresponding QCD corrections.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

Prostate artery Embolisation Assessment of Safety and feasibilitY (P-EASY): a potential alternative to long-term medical therapy for benign prostate hyperplasia.

OBJECTIVES: To assess the safety, short-term efficacy and early functional results of prostate artery embolisation (PAE), an emerging minimally invasive treatment for symptomatic benign prostate hyperplasia (BPH). PATIENTS AND METHODS: In all, 51 men with BPH (prostate size >40 mL) causing moderate-severe lower urinary tract symptoms, who had either failed or ceased medical therapy and had declined or were considered unsuitable for surgical intervention, were recruited to this study. All men underwent baseline clinical assessment, PAE, and 3-month follow-up. The primary endpoints of this study were safety and feasibility. Safety was measured by the incidence of post-PAE adverse events and feasibility was defined by technical success. Secondary endpoints were changes in the International Prostate Symptom Score (IPSS) and quality of life (QoL) score at 3 months after PAE. RESULTS: There were no serious adverse events and all procedures were technically successful. For non-catheterised patients, improvement in IPSS and QoL was reported in 95.1% of cases (P < 0.001). The mean reductions in IPSS and QoL were 18.8 points (80.7%) (P < 0.001) and 3.8 points (80.6%) (P < 0.001), respectively. Of the 30 non-indwelling-catheter-dependent men on medical therapy, 23 men were able to completely cease all medications, with all but one of the remaining men reporting significant improvements in IPSS and QoL score. CONCLUSION: PAE is a technically feasible and safe procedure, with excellent short-term efficacy. High rates of patient satisfaction were achieved in this study, along with significant reductions in prostate symptoms and improvements in QoL. PAE may be an alternative to long-term use of medical therapy for symptoms due to BPH.

A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma.

BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide. Patients in the Phase 2 Filanesib plus dexamethasone cohort (N = 55) had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout Phase 2. RESULTS: Patients in each cohort had received a median of ≥6 prior therapies. The most common dose-limiting toxicities were febrile neutropenia and mucosal inflammation. In Phase 2, Grade 3 and 4 cytopenias were reported in approximately 50% of patients. Nonhematologic toxicities were infrequent. Phase 2 response rates (partial responses or better) were 16% (single agent) and 15% (Filanesib plus dexamethasone). All responding patients had low baseline levels of α1-acid glycoprotein, a potential selective biomarker. CONCLUSIONS: Filanesib 1.50 mg/m2 /day administered with prophylactic filgrastim has a manageable safety profile and encouraging activity in heavily pretreated patients This study is registered at www.clinicaltrials.gov as NCT00821249. Cancer 2017;123:4617-4630. © 2017 American Cancer Society.

A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma.

BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2 /day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2 /day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2 /day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.

Automated 3D quantitative assessment and measurement of alpha angles from the femoral head-neck junction using MR imaging.

To develop an automated approach for 3D quantitative assessment and measurement of alpha angles from the femoral head-neck (FHN) junction using bone models derived from magnetic resonance (MR) images of the hip joint.Bilateral MR images of the hip joints were acquired from 30 male volunteers (healthy active individuals and high-performance athletes, aged 18­49 years) using a water-excited 3D dual echo steady state (DESS) sequence. In a subset of these subjects (18 water-polo players), additional True Fast Imaging with Steady-state Precession (TrueFISP) images were acquired from the right hip joint. For both MR image sets, an active shape model based algorithm was used to generate automated 3D bone reconstructions of the proximal femur. Subsequently, a local coordinate system of the femur was constructed to compute a 2D shape map to project femoral head sphericity for calculation of alpha angles around the FHN junction. To evaluate automated alpha angle measures, manual analyses were performed on anterosuperior and anterior radial MR slices from the FHN junction that were automatically reformatted using the constructed coordinate system.High intra- and inter-rater reliability (intra-class correlation coefficients > 0.95) was found for manual alpha angle measurements from the auto-extracted anterosuperior and anterior radial slices. Strong correlations were observed between manual and automatic measures of alpha angles for anterosuperior (r = 0.84) and anterior (r = 0.92) FHN positions. For matched DESS and TrueFISP images, there were no significant differences between automated alpha angle measures obtained from the upper anterior quadrant of the FHN junction (two-way repeated measures ANOVA, F < 0.01, p = 0.98).Our automatic 3D method analysed MR images of the hip joints to generate alpha angle measures around the FHN junction circumference with very good reliability and reproducibility. This work has the potential to improve analyses of cam-type lesions of the FHN junction for large-scale morphometric and clinical MR investigations of the human hip region.

Transarterial treatment of colorectal cancer liver metastases with irinotecan-loaded drug-eluting beads: technical recommendations.

Transcatheter hepatic arterial administration of irinotecan-loaded drug-eluting beads (DEBIRI) is used to treat liver-only or liver-dominant metastatic disease from colorectal cancer (CRC). Eligibility for DEBIRI should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of DEBIRI technique and protocols would be expected to lead to improved efficacy and safety. The present article provides a set of technical recommendations for the use of DEBIRI in the treatment of hepatic CRC metastases.

Segmentation of the quadratus lumborum muscle using statistical shape modeling.

PURPOSE: To compare automated segmentation of the quadratus lumborum (QL) based on statistical shape modeling (SSM) with conventional manual processing of magnetic resonance (MR) images for segmentation of this paraspinal muscle. MATERIALS AND METHODS: The automated SSM scheme for QL segmentation was developed using an MR database of 7 mm axial images of the lumbar region from 20 subjects (cricket fast bowlers and athletic controls). Specifically, a hierarchical 3D-SSM scheme for segmentation of the QL, and surrounding psoas major (PS) and erector spinae+multifidus (ES+MT) musculature, was implemented after image preprocessing (bias field correction, partial volume interpolation) followed by image registration procedures to develop average and probabilistic MR atlases for initializing and constraining the SSM segmentation of the QL. The automated and manual QL segmentations were compared using spatial overlap and average surface distance metrics. RESULTS: The spatial overlap between the automated SSM and manual segmentations had a median Dice similarity metric of 0.87 (mean = 0.86, SD = 0.08) and mean average surface distance of 1.26 mm (SD = 0.61) and 1.32 mm (SD = 0.60) for the right and left QL muscles, respectively. CONCLUSION: The current SSM scheme represents a promising approach for future automated morphometric analyses of the QL and other paraspinal muscles from MR images.

Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520.

Kinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis. The majority (three of four) of cell lines underwent mitotic arrest, with apoptosis occurring in mitosis within 24 to 30 hours. The remaining line (NCI H929) is temporally refractory to ARRY-520 treatment, undergoing mitotic slippage and subsequently peaking in apoptotic markers after 72 hours of treatment, while most cells are in interphase. Interestingly, loss of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) coincided with mitotic cell death. Stabilization of Mcl-1 resulted in a delayed onset of apoptosis, whereas enforced downregulation of Mcl-1 increased cell death in response to KSP inhibition. Thus, variation in responses to KSP inhibition is governed by a balance between survival proteins and spindle checkpoint integrity. Cells relying on short-lived survival proteins during mitosis are more likely to undergo apoptosis in response to KSP inhibition. We propose that patients with hematologic malignancies, which rely on Mcl-1, would therefore be good candidates for treatment with KSP inhibitors.

ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models.

AIM: Profiling the efficacy and pharmacodynamic activity of the kinesin spindle protein (KSP) inhibitor ARRY-520 will aid the identification of responsive tumor types and pharmacodynamic profiles that correlate with activity. MATERIALS AND METHODS: In vivo activity was evaluated in a diverse panel of 16 different tumor xenograft models. Pharmacodynamic activity was evaluated in selected models. RESULTS: ARRY-520 had low nanomolar antiproliferative activity in tumor cell lines. Monopolar spindles were formed at active potencies. Partial or complete responses were observed in 13/16 xenograft models. Hematological tumors were particularly sensitive, with a 100% complete response rate in some models. Maintenance of mitotic block for a sufficient length of time for cells to lose survival signals and progress to apoptosis was a key component of the mechanism of activity. ARRY-520 was also active in several taxane resistant models. CONCLUSION: The data provide a rationale for clinical evaluation of the activity of ARRY-520 in hematological carcinomas and taxane-resistant tumors.

SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples.

PURPOSE: SNS-032 (formerly BMS-387032) is a potent, selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9, currently in phase 1 clinical trial for chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We used the MM cell line RPMI-8226 to evaluate the relationship between duration of SNS-032 exposure, target modulation of CDKs 2, 7 and 9, and induction of apoptosis. We also assessed target modulation in patient peripheral blood mononuclear cells (PBMCs) from phase 1 solid tumor patients treated with SNS-032. METHODS: Proliferation and colony forming assays were used to evaluate cytotoxicity, Western blot analyses to evaluate target modulation, FACS analysis to assess cell cycle distribution, RT-PCR to evaluate transcriptional inhibition. RESULTS: SNS-032 blocks the cell cycle via inhibition of CDKs 2 and 7, and transcription via inhibition of CDKs 7 and 9. Treatment of RPMI-8226 MM cells at 300 nM (IC(90)) for 6 h was sufficient for commitment to apoptosis. This correlated with inhibition of CDKs 2, 7 and 9, as reflected in substrate signaling molecules. SNS-032 activity was unaffected by human serum. Target modulation was observed in PBMC from treated patients. CONCLUSIONS: These results demonstrate SNS-032 target modulation of CDKs 2, 7 and 9, and establish 6 h exposure as sufficient to commit RPMI-8226 MM cells to apoptosis. Combined with the demonstration of target modulation in PBMC from phase 1 solid tumor patients treated with SNS-032, these data support the ongoing clinical study of SNS-032 in MM and CLL.

Alterations in muscle attenuation following detraining and retraining in resistance-trained older adults.

BACKGROUND: Aging skeletal muscle is characterized not only by a reduction in size (sarcopenia) and strength but also by an increase in fatty infiltration (myosteatosis). An effective countermeasure to sarcopenia is resistance exercise; however, its effect on fatty infiltration is less clear. OBJECTIVE: To examine in resistance-trained older persons whether muscle attenuation, a noninvasive measure of muscle density reflecting intramuscular lipid content, is altered with training status. METHODS: Thirteen healthy community-dwelling men and women aged 65-83 years (body mass index 27.0+/-1.2, mean+/-SE) had computed-tomography scans of the mid-thigh performed following 24 weeks of training, 24 weeks of detraining, and 12 weeks of retraining. Training and retraining were undertaken twice weekly for several upper- and lower-body muscle groups. Skeletal muscle attenuation in Hounsfield units (HU) as well as mid-thigh muscle volume was obtained for the quadriceps and hamstrings. Muscle strength was assessed by 1-repetition maximum and physical function by a battery of tests. RESULTS: The average change in muscle strength following training, detraining and retraining was 48.8+/-2.9%, -17.6+/-1.3%, and 19.8+/-2.0%, respectively. Strength changes were accompanied by significant alterations in muscle density (p<0.001), with the quadriceps HU decreasing by 7.7+/-1.0% following detraining and increasing by 5.4+/-0.5% with retraining. For the hamstrings HU measure, detraining and retraining resulted in an 11.9+/-1.4% loss and a 5.5+/-1.8% gain, respectively. There was no significant change in muscle volume. CONCLUSION: Cessation of resistance exercise in trained older persons increases the fatty infiltration of muscle, while resumption of exercise decreases it. Monitoring changes in both muscle size and fat infiltration may enable a more comprehensive assessment of exercise in combating age-related muscular changes.

A diaminocyclohexyl analog of SNS-032 with improved permeability and bioavailability properties.

The identification of a selective CDK2, 7, 9 inhibitor 4 with improved permeability is described. Compound 4 exhibits comparable CDK selectivity profile to SNS-032, but shows improved permeability and higher bioavailability in mice.

Modifications of the isonipecotic acid fragment of SNS-032: analogs with improved permeability and lower efflux ratio.

Modifications of the isonipecotic acid fragment of SNS-032 results in analogs which are more permeable and lower effluxed than SNS-032. The enantiomerically pure synthesis and the in vivo profile of analog 20 is described.

Quadratus lumborum asymmetry and L4 pars injury in fast bowlers: a prospective MR study.

PURPOSE: This prospective study examined the association between quadratus lumborum (QL) asymmetry and the development of symptomatic pars interarticularis lesions in the lumbar spine of adolescent cricket fast bowlers. METHODS: Annual magnetic resonance imaging was used to measure QL volume asymmetry and for identifying pars lesions of the lumbar vertebrae in fast bowlers (N=51) and a control group of swimmers (N=18). Manual segmentation of axial images spanning the lumbar spine was performed to calculate percent QL asymmetry relative to the bowling- or throwing- (swimmers) arm side. Asymmetry above 100% indicated a larger QL volume on the bowling- (throwing) arm side. RESULTS: The mean QL asymmetry in bowlers of 110.5% (SD=12.1%) was significantly different from the 96.6% (SD=5.0%) asymmetry in swimmers (t=6.75, P

Pars interarticularis stress lesions in the lumbar spine of cricket fast bowlers.

PURPOSE: This prospective magnetic resonance (MR) imaging study investigated the development of symptomatic pars lesions in the lumbar spine of adolescent cricket fast bowlers. METHODS: Annual MR examinations of the lumbar spine in male fast bowlers (N = 51) and swimmers (N = 20) without a prestudy history of symptomatic back injury were conducted to identify stress-induced pars injuries over 4 and 2 yr periods, respectively. RESULTS: Symptomatic L4 and L5 pars lesions developed in 11 of 51 and 1 of 51 of the bowlers, respectively. Preexisting L5 lesions were observed in both bowlers (10 of 51) and swimmers (4 of 20). No significant difference existed between the proportion of bowlers and swimmers with preexisting L5 lesions (P = 1.00, Fisher's exact test). In contrast, bowlers had a significantly greater proportion of L4 pars lesions compared with swimmers, with 22% of the bowlers developing L4 injuries during the study, whereas there were no L4 lesions in the swimmers (P = 0.027, Fisher's exact test). The symptomatic L4 lesions in the bowlers developed between 15 and 17 yr of age, and all were unilateral lesions lateralized to the nonbowling-arm side. The MR characteristics of the L4 pars lesions were consistent with a stress fracture through the cortical bone. Of the acquired L4 lesions in the bowlers, 4 of 11 and 7 of 11 developed in individuals with and without preexisting L5 defects, respectively. No significant association existed between the acquired L4 pars lesions and preexisting L5 defects in the bowlers (P = 0.216, Fisher's exact test). CONCLUSION: Fast bowling was directly associated with the development of symptomatic pars lesions of the lumbar spine, particularly unilateral L4 stress lesions, in a significant proportion of the adolescent bowlers examined in this prospective MR study.