NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts.

Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).

Volume Load and Neuromuscular Fatigue During an Acute Bout of Agonist-Antagonist Paired-Set vs. Traditional-Set Training.

The purpose of this study was to investigate the acute effects of performing paired-set (PS) vs. traditional-set (TS) training over 3 consecutive sets, on volume load and electromyographic fatigue parameters of the latissimus dorsi, biceps brachii, pectoralis major, and triceps brachii muscles. Fifteen trained men performed 2 testing protocols (TS and PS) using 10 repetition maximum loads. The TS protocol consisted of 3 sets of bench press (BP) followed by 3 sets of wide-grip seated row (SR). The PS consisted of 3 sets of BP and 3 sets of SR performed in an alternating manner. Volume load was calculated as load × repetitions. The electromyographic signal, time (CRMS) and frequency (Cf5) domain, parameters were recorded during SR. Under the PS protocol, sets of SR were performed immediately after the sets of BP. A 2-minute rest interval between the completion of the set of SR and the subsequent set of BP was implemented (e.g., between PSs). Under the TS protocol, 2-minute rest intervals were implemented between all sets. BP and SR volume loads decreased significantly from set 1 to set 2 and from set 2 to set 3 under both conditions. Volume load was greater for all sets of both exercises under PS as compared with TS. Muscle fatigue indices were greater under PS as compared with TS. In general, these results indicate that as compared with TS, PS produced a greater training volume in less time and may induce greater fatigue and thereby provide an enhanced training stimulus.

Photoredox Mediated Nickel Catalyzed Cross-Coupling of Thiols With Aryl and Heteroaryl Iodides via Thiyl Radicals.

Ni-catalyzed cross-couplings of aryl, benzyl, and alkyl thiols with aryl and heteroaryl iodides were accomplished in the presence of an Ir-photoredox catalyst. Highly chemoselective C-S cross-coupling was achieved versus competitive C-O and C-N cross-couplings. This C-S cross-coupling method exhibits remarkable functional group tolerance, and the reactions can be carried out in the presence of molecular oxygen. Mechanistic investigations indicated that the reaction proceeded through transient Ni(I)-species and thiyl radicals. Distinct from nickel-catalyzed cross-coupling reactions involving carbon-centered radicals, control experiments and spectroscopic studies suggest that this C-S cross-coupling reaction does not involve a Ni(0)-species.

Practical and Broadly Applicable Catalytic Enantioselective Additions of Allyl-B(pin) Compounds to Ketones and α-Ketoesters.

A set of broadly applicable methods for efficient catalytic additions of easy-to-handle allyl-B(pin) (pin=pinacolato) compounds to ketones and acyclic α-ketoesters was developed. Accordingly, a large array of tertiary alcohols can be obtained in 60 to >98 % yield and up to 99:1 enantiomeric ratio. At the heart of this development is rational alteration of the structures of the small-molecule aminophenol-based catalysts. Notably, with ketones, increasing the size of a catalyst moiety (tBu to SiPh3 ) results in much higher enantioselectivity. With α-ketoesters, on the other hand, not only does the opposite hold true, since Me substitution leads to substantially higher enantioselectivity, but the sense of the selectivity is reversed as well.

Highly Chemoselective Iridium Photoredox and Nickel Catalysis for the Cross-Coupling of Primary Aryl Amines with Aryl Halides.

A visible-light-promoted iridium photoredox and nickel dual-catalyzed cross-coupling procedure for the formation C-N bonds has been developed. With this method, various aryl amines were chemoselectively cross-coupled with electronically and sterically diverse aryl iodides and bromides to forge the corresponding C-N bonds, which are of high interest to the pharmaceutical industries. Aryl iodides were found to be a more efficient electrophilic coupling partner. The coupling reactions were carried out at room temperature without the rigorous exclusion of molecular oxygen, thus making this newly developed Ir-photoredox/Ni dual-catalyzed procedure very mild and operationally simple.

Effects of Molecular Oxygen, Solvent, and Light on Iridium-Photoredox/Nickel Dual-Catalyzed Cross-Coupling Reactions.

In order to achieve reproducibility during iridium-photoredox and nickel dual-catalyzed sp(3)-sp(2) carbon-carbon bond-forming reactions, we investigated the role that molecular oxygen (O2), solvent and light-source (CF lamp or blue LED) play in a variety of Ir-photoredox mediated transformations. The presence of O2 was discovered to be important for catalyst activation when air-stable Ni(II) precatalysts were used in DMF under CF lamp irradiation; however, O2 was not required for catalysis when conducted with Ni(COD)2 in the same reaction system. O2 is believed to promote rapid reduction of the Ni(II) precatalyst by Ir(II) to Ni(0). In addition to O2, the effects that solvent and light-source have on the dual-catalyzed decarboxylative cross-coupling reactions will be discussed. These findings have enabled us to develop a more robust dual-catalyzed decarboxylative cross-coupling protocol.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Changes in the athletic profile of elite college American football players.

The purpose of this study was to compare positional anthropometric and National Football League (NFL) Combine performance levels in elite college American football players over the 3-year period from 1999 to 2001 to the 3-year period from 2008 to 2010. The sample included 15 offensive and defensive positions, and only those players invited to the combine and subsequently drafted in the same year (n = 1,712) were included in the study. Data from 10 combine physical tests were examined, including weight; height; the 9.1-, 18.3-, and 36.6-m sprints; the vertical and horizontal jumps; the 18.3-m shuttle run; the 3-cone drill; and the 102.1-kg bench press for maximum repetitions. Independent samples t-tests detected differences for each of the 15 positions (p < 0.05). There were no discernible trends in height and weight over the period in question, whereas players in the more recent group significantly improved performance in straight sprinting, the 3-cone drill, and the horizontal jump. Findings suggest that these tests better reflect characteristics such as explosiveness and first-step quickness as compared with the 18.3-m shuttle and the vertical jump, and that such characteristics have become more highly sought after by NFL coaches and scouts. The results of the present research suggest that the position-specific profiles changed over a relatively short period of time. Coaches and practitioners will be able to use the findings of this research to better prepare athletes for entry into the NFL.

The normalization of explosive functional movements in a diverse population of elite American football players.

The objective of this study was to investigate the need to normalize, for body mass, explosive functional tasks in a population exhibiting diverse body masses. Measures investigated in elite college American football players attending the National Football League's annual combine (n = 1,136) were the 9.1-, 18.3-, and 36.6-m sprints, vertical and horizontal jumps, 18.3-m shuttle, and 3-cone drill. To determine the relationship between body mass and performance outcomes, Pearson's correlation coefficients (r) were generated using log-transformed data. Task-specific allometric exponents, accounting for body mass, were also determined. The strength of the correlations suggests that sprint and jump abilities are associated with body mass, whereas change-of-direction ability is not. The determined allometric exponents range between 0.296 and -0.463 for the sprint and jump tasks and are -0.022 and -0.006 for the 18.3-m shuttle and the 3-cone drill, respectively. In populations exhibiting relatively large variations in body mass, normalization of sprint and jump abilities is recommended, whereas normalization of change-of-direction ability is unwarranted. Novel suggestions derived from the present research are that sprint and jump abilities in diverse populations warrant normalization and that physical attributes associated with explosive functional movements deserve attribute-specific consideration when contemplating normalization.

Relationships between National Football League combine performance measures.

The purpose of this study was to investigate the relationships between the athletic skills measured at the National Football League (NFL) combine. The combine comprises the following tests: 36.6-m sprint with split times at 9.1 and 18.3 m, vertical and horizontal jumps, 18.3-m shuttle run, 3-cone drill, and 102.1-kg bench press. Draftees to the NFL who participated in the annual combine from 2005 to 2009 were included in the study (n = 1,136). Pearson's (r) correlations were calculated to determine the relationships between the tests, and coefficients of determination (r) were used to determine common variance. The 9.1-, 18.3-, and 36.6-m sprint times are nearly perfectly correlated (r ranges from 0.900 to 0.967) as are the change-of-direction ability tests, 18.3-m shuttle run, and 3-cone drill (r = 0.948), suggesting similar skills are being measured. Performance in both jumping tasks is more strongly associated with longer sprint distances, suggesting mechanisms such as the stretch-shortening cycle may be more important at maximal, or near-maximal, speeds. The correlations between change-of-direction ability and sprinting and jumping are generally much weaker (r ranges from 0.250 to -0.653), suggesting less association and independent motor skills. Although not particularly large correlation coefficients, bench press performance is positively correlated with outcomes in all running drills and inversely correlated with jump abilities, suggesting that in the observed cohort, upper body strength may be of little benefit to these tasks. Incorporation of a nonacceleration influenced (i.e., moving start) measure of maximal speed may be preferred if the intention of a test battery is to measure independent motor skills. Further, when constructing test batteries, either the 18.3-m shuttle or 3-cone drill is likely sufficient as a measure of change-of-direction ability. Test batteries should be constructed to measure independent motor skills.

Movement demands in Australian rules football as indicators of muscle damage.

The purpose of this study was to determine if there is an association between variables that describe movements in an Australian Rules football (ARF) game with muscle damage. Fourteen elite junior ARF players were monitored with a global positioning system (GPS) during a match, and muscle damage was estimated by determining creatine kinase (CK) 24 hours postmatch. The players were median split based on CK levels, into a high and low CK group, and the groups were compared with independent t-tests. The primary finding was that the group that experienced greater muscle damage (high CK group) generally covered significantly (p < 0.05) greater distances. This was the case for running speeds between 4 and 7 m·s(-1) and, with the exception of high acceleration, all intensities of acceleration and deceleration. The high, as compared with the low, CK group also produced a significantly greater (42%) "player load." All of these significant differences were accompanied by large effect sizes. Group-specific Pearson (r) correlations between CK level and GPS variables suggest that a certain volume of movement is required before the elicitation of a positive relationship beyond trivial or small. Correlations between CK and running speeds >4 m·s(-1) and moderate-high acceleration and deceleration were negative in the low CK (lesser volumes) group. With the exception of low-intensity acceleration/deceleration, the same relationships were positive and generally of a moderate-to-large magnitude in the high CK (greater volumes) group. It may be that a certain volume of movement is required for that movement to be strongly associated with CK levels. It was concluded that selected GPS variables obtained from ARF games can be used as indicators of muscle damage, and this information may be used to individualize recovery strategies after games.

Positional relationships between various sprint and jump abilities in elite American football players.

The purpose of this study was to investigate positional relationships between sprint and jump abilities and body mass in elite college American football players (n = 1,136). Data from the annual National Football League combine over the years 2005-2009 were examined. The measures included for examination were the 9.1-, 18.3-, 36.6-, and flying 18.3-m sprints and the vertical and horizontal jumps. Pearson's correlation coefficients (r) were calculated to determine the relationships between the tests, and coefficients of determination (r2) were used to determine common variance. With the exception of the relationship between the 9.1-m and the flying 18.3-m sprints, the relationships between all sprints are very strong. Vertical jump ability is more strongly associated with maximum speed, as compared with acceleration. Horizontal jump ability is similarly associated with maximum speed and acceleration. The 9.1-, 18.3-, and flying 18.3-m sprints and the jump tests would appear to measure independent skills. Stationary start sprints up to 36.6 m appear to be heavily influenced by acceleration and may thus measure similar characteristics. The flying 18.3-m sprint is recommended as a measure of maximum speed. Body mass was most strongly associated with performance in the lineman group. When body mass was controlled for, correlations weakened across all the groups. The role of body mass remains unclear. Regardless of sport, the present research supports the notion that the relationships between various sprint and jump abilities warrant positional consideration. Coaches and practitioners will be able to use the findings of this research to better test and monitor athletes requiring different skills.

The effect of training volume on lower-body strength.

The objective of this study was to examine the chronic effects on lower-body strength in resistance trained men of performing varying training volumes over 6 weeks. A pretest and posttest design was used to investigate the effects on 1-repetition maximum (1RM) squat strength. Also, 1RM testing was performed at 3 weeks. Participants were randomly assigned to an intensity-matched (80% of 1RM) low (1-SET), moderate (4-SET), or high (8-SET) volume condition. In addition to significant strength increases in all groups at the end of the 6-week period, increases were observed at 3 weeks under the 4- and 8-SET conditions, which were greater than the improvement under the 1-SET condition. At 6 weeks, the magnitude of improvement was significantly greater for the 8-SET, as compared with that of the 1-SET group. The magnitude of improvement elicited in the 4-SET group was not different from that of the 1-SET or 8-SET groups. The results suggest that "high" volumes (i.e., >4 sets) are associated with enhanced strength development but that "moderate" volumes offer no advantage. Practitioners should be aware that strength development may be dependent on appropriate volume doses and training duration.

Studies on the synthesis of apoptolidin: synthesis of a C1-C27 fragment of apoptolidin D.

Synthesis of a C(1)-C(27) fragment, a key intermediate in the synthesis of apoptolidin D, is reported. The synthesis involves a combination of Heck coupling and Horner-Wadsworth-Emmons reaction for the C(1)-C(7) trienoate portion and an efficient Suzuki cross-coupling protocol for the C(10)-C(13) diene portion.

Positional physical characteristics of players drafted into the National Football League.

To investigate the positional physical requirements necessary to be drafted into the National Football League (NFL), data from the annual NFL combine over the years 2005-2009 were examined. Only those players invited to the combine and subsequently drafted in the same year (n = 1,136) were included in the study. Data from 8 combine physical performance tests were examined for 15 positions. Combine measures evaluated for the center, cornerback, defensive end, defensive tackle, free safety, fullback, inside linebacker, offensive guard, offensive tackle, outside linebacker, quarterback, running back, strong safety, tight end, and wide receiver positions were the 9.1-, 18.3-, and 36.6-m sprints, the vertical and broad jumps, the 18.3-m shuttle run, the 3-cone drill, and the 102.1-kg bench press for maximum repetitions and, from this, a predicted measure of 1 repetition maximum. A 1-way analysis of variance detected differences in all 9 performance measures (p < 0.01). Post hoc independent t-tests indicated that over most tests many positions exhibited outcomes significantly different from most other positions. Generally, lineman positions performed inferiorly in sprint, jump and change-of-direction ability measures and superiorly in the upper body strength measures. Conversely, defensive back positions were the worst performers in the upper body strength test, and wide receivers and defensive backs were the best performers in all other measures. In general, offensive and defensive positions that commonly compete directly against one another display similar physical characteristics. Any advantages (statistically significant and not) between positions in direct competition were consistently in favor of defensive positions. The results of the present research present position-specific profiles for each of 15 positions. Coaches and practitioners will be able to use the findings of this research to better prepare athletes for entry into the NFL.

Core stability exercises in individuals with and without chronic nonspecific low back pain.

Marshall, PWM, Desai, I, and Robbins, DW. Core stability exercises in individuals with and without chronic nonspecific low back pain. J Strength Cond Res 25(12): 3404-3411, 2011-The aim of this study was to measure trunk muscle activity during several commonly used exercises in individuals with and without low back pain (LBP). Abdominal bracing was investigated as an exercise modification that may increase the acute training stimulus. After an initial familiarization session, 10 patients with LBP and 10 matched controls performed 5 different exercises (quadruped, side bridge, modified push-up, squat, shoulder flexion) with and without abdominal bracing. Trunk muscle activity and lumbar range of motion (LROM) were measured during all exercises. Muscle activity was measured bilaterally during each exercise from rectus abdominis (RA), external obliques (EO), and lumbar erector spinae (ES) with pairs of surface electrodes. Recorded signals were normalized to a percentage of maximal voluntary contractions performed for each muscle. The ES activity was lower for the LBP group during the quadruped (p < 0.05) and higher for RA and EO during the side bridge (p < 0.001), compared to for the healthy controls. Higher muscle activity was observed across exercises in an inconsistent pattern when abdominal bracing was used during exercise. The LROM was no different between groups for any exercise. The lack of worsening of symptoms in the LBP group and similar LROM observed between groups suggest that all exercises investigated in this study are of use in rehabilitating LBP patients. The widespread use of abdominal bracing in clinical practice, whether it be for patients with LBP or healthy individuals, may not be justified unless symptoms of spinal instability are identified.

Iridium-catalyzed, silyl-directed borylation of nitrogen-containing heterocycles.

Selective methods for the functionalization of indoles and other nitrogen heterocycles would provide access to the core structures of many natural products and pharmaceuticals. Although there are many methods and strategies for the synthesis of substituted indoles or functionalization of the azole ring, strategies for the selective functionalization of the benzo-fused portion of the indole skeleton, particularly the 7-position, are less common. We report a one-pot, iridium-catalyzed, silyl-directed C-H borylation of indoles at the 7-position. This process occurs in high yield with a variety of substituted indoles, and conversions of the 7-borylindole products to 7-aryl-, 7-cinnamyl-, and 7-haloindoles are demonstrated. The Ir-catalyzed, silyl-directed C-H borylation also occurs with several other nitrogen heterocycles, including carbazole, phenothiazines, and tetrahydroquinoline. The utility of this methodology is highlighted by the one-pot synthesis of a member of the pyrrolophenanthridone class of alkaloid natural products.

The National Football League (NFL) combine: does normalized data better predict performance in the NFL draft?

The objective of this study was to investigate the predictive ability of National Football League (NFL) combine physical test data to predict draft order over the years 2005-2009. The NFL combine provides a setting in which NFL personnel can evaluate top draft prospects. The predictive ability of combine data in its raw form and when normalized in both a ratio and allometric manner was examined for 17 positions. Data from 8 combine physical performance tests were correlated with draft order to determine the direction and strength of relationship between the various combine measures and draft order. Players invited to the combine and subsequently drafted in the same year (n = 1,155) were included in the study. The primary finding was that performance in the combine physical test battery, whether normalized or not, has little association with draft success. In terms of predicting draft order from outcomes of the 8 tests making up the combine battery, normalized data provided no advantage over raw data. Of the 8 performance measures investigated, straight sprint time and jumping ability seem to hold the most weight with NFL personnel responsible for draft decisions. The NFL should consider revising the combine test battery to reflect the physical characteristics it deems important. It may be that NFL teams are more interested in attributes other than the purely physical traits reflected in the combine test battery. Players with aspirations of entering the NFL may be well advised to develop mental and technical skills in addition to developing the physical characteristics necessary to optimize performance.

The effect of an upper-body agonist-antagonist resistance training protocol on volume load and efficiency.

The objective of this study was to investigate the acute effects on volume load (VL) (load × repetitions) of performing paired set (PS) vs. traditional set (TS) training over 3 consecutive sets. After a familiarization session 16 trained men performed 2 testing protocols using 4 repetition maximum loads: TS (3 sets of bench pull followed by 3 sets of bench press performed in approximately 10 minutes) or PS (3 sets of bench pull and 3 sets of bench press performed in an alternating manner in approximately 10 minutes). Bench pull and bench press VL decreased significantly from set 1 to set 2 and from set 2 to set 3 under both the PS and TS conditions (p < 0.05). Bench pull and bench press VL per set were significantly less under TS as compared to PS over all sets, with the exception of the first set (bench pull set 1) (p < 0.05). Session totals for bench pull and bench press VL were significantly less under TS as compared to PS (p < 0.05). Paired set was determined to be more efficient (VL/time) as compared to TS. The data suggest that a 2-minute rest interval between sets (TS), or a 4-minute rest interval between similar sets (PS), may not be adequate to maintain VL. The data further suggest that PS training may be more effective than TS training in terms of VL maintenance and more efficient. Paired set training would appear to be an efficient method of exercise. Practitioners wishing to maximize work completed per unit of time may be well advised to consider PS training.

Agonist-antagonist paired set resistance training: a brief review.

Agonist-antagonist paired set (APS) training refers to the coupling of agonist and antagonist exercises, performed in an alternating manner with rest intervals between each set. The purpose of this review is to identify the proposed benefits and possible underlying mechanisms of APS training and to suggest how APS training may be exploited. Furthermore, areas deserving of further research attention will be presented. This review will also suggest a common terminology (i.e., APS training) for describing training modalities that alternate agonist and antagonist exercises. Although somewhat equivocal, evidence exists supporting the use of APS as a means of enhancing short-term power measures. Evidence also exists suggesting APS training is an efficacious and efficient means of developing strength and power. Time-efficient methods of developing strength and power would have benefits for athletes and the general population. Athletes able to spend less time developing strength and power would have more time to devote to other aspects of performance or other unrelated tasks. The general population may be more willing to adhere to less time-consuming resistance training programs that offer similar results, as compared to more time-consuming programs. This review concludes that the practical applicability of APS training in terms of acute performance enhancement is limited. However, the use of APS training as an efficacious and time-effective method for developing strength and power may hold some merit.