Allen Li

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.

STAGING OF KÜMMELL'S DISEASE

Kummells disease is defined as delayed post-traumatic vertebral collapse, common in osteoporotic people with/without a trauma history. Its clinical course is progressive, and treatment modalities ...

Erratum: The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma (Nature (2012) 486 (266-270) DOI: 10.1038/nature11114)

This corrects the article DOI: 10.1038/nature11114

Erratum: Corrigendum: The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

This corrects the article DOI: 10.1038/nature11114

Corrigendum: The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

This corrects the article DOI: 10.1038/nature11114

Transpedicle body augmenter for vertebral augmentation in symptomatic multiple osteoporotic compression fractures.

Background: Multiple osteoporotic vertebral compression fractures (VCFs) have been treated with polymethylmethacrylate augmentation; however, there are cement complications and long-term fracture healing that are unknown. Transpedicle body augmenter (a porous titanium spacer) has been reported as an internal support to reconstruct the vertebral body combining short-segment fixation in burst fracture and Kümmells disease with cord compression. Transpedicle body augmenter for vertebral augmentation (TpBA) also has been reported successfully in treating single painful VCF and vertebral metastasis lesions including pending fractures and pathologic compression fractures. To test the hypothesis that TpBA can effectively and safely treat the symptomatic multiple VCFs, this retrospective study was done by analyzing the radiographic and clinical results. Materials and Methods: We retrospectively reviewed clinical and radiographic results of TpBA for symptomatic multiple (more than two levels) VCFs in 62 patients with a total of 236 levels, i.e. 3.8 VCFs per patient. Manual reduction and TpBA via paramedian incisions with blunt dissection were done. One incision was made for two continuous levels and alternative side was selected for next incision. Mean age was 74.3 years (range, 62-87 years), and female-male ratio was 5.2:1. Anterior vertebral height and wedge angle by radiographic findings were measured at preoperative, initial follow-up and final follow-up. Clinical results were assessed by questionnaires and clinical observations. By July 2008, 58 patients returned to answer the questionnaire including quantification of pain on the visual analog scale, the response to operations (better, same, or worse after operation), returned to their pre-fracture function (yes/no) and satisfaction (a scale of 0 = completely dissatisfied to 10 = completely satisfied). Results: The mean symptom duration was 7 months, and follow-up, 48 months. The average operation time was 21 min per level, blood loss was 74 cc per level and hospitalization was 4.4 days. No patient had neurological deterioration. There was no dislodgement of implant in the final visit. Forty-eight patients (77.4%) could walk within 6-8 h after operation and the others, within 24 h. The anterior vertebral restoration was 7.3 mm initially and 6.2 mm at final follow-up. Wedge angle correction was 10.4° initially and was 9.3° at final follow-up. Pain, by the visual analog scale, was 8.5 preoperatively, 2.7 at day 7 follow-up and 2.9 at final follow-up. By the questionnaire, 52 of 58 respondents reported a decrease in discomfort after TpBA and 48 of 58 patients reported a return to normal activity after operation. The final satisfaction rate was 89.7%. Discussion: The symptoms of multiple osteoporotic compression fracture may be due to unstable fracture, radiculopathy, and global traumatic kyphosis with posture changes, which can be corrected by multiple TpBA. The transpedicle body augmenter was initially stabilized by the sinking and locking mechanism and finally by bone ingrowth. Conclusions: TpBA via a minimally invasive method led to early and medium-term clinical improvements and anatomic restoration of multiple symptomatic VCFs.

Long-term results of transpedicle body augmenter in treating burst fractures

Background: Short-segment fixation alone to treat thoracolumbar burst fractures is common but it has a 20-50% incidence of implant failure and rekyphosis. A transpedicle body augmenter (TpBA) to reinforce the vertebral body via posterior approach has been reported to prevent implant failure and increase the clinical success rate in treating burst fracture. This article is to evaluate the longterm results of short-segment fixation with TpBA for treatment of thoracolumbar burst fractures. Materials and Methods: Patients included in the study had a single-level burst fracture involving T11-L2 and no distraction or rotation element with limited neurological deficit. Patients in the control group (n = 42) were treated with short-segment posterior instrumentation alone, whereas patients in the augmented group (n = 90) were treated with a titanium spacer designed for transpedicle body reconstruction. The followup was 48-101 months. The radiographic and clinical results were evaluated and compared by Students t test and Fishers exact test. Results: The blood loss, operation time and hospitalization were similar in both the groups. The immediate postoperative anterior vertebral restoration rate of the augmented group was similar to that of the control group (97.6% ± 2.4% vs. 96.6% ± 3.2%). The final anterior vertebral restoration was greater in the augmented group than in the control group (93.3% ± 3.4% vs. 62.5% ± 11.2%). Immediate postoperative kyphotic angles were not significantly different between the groups (3.0° ± 1.8° vs. 5.1° ± 2.3°). The final kyphotic angles were less in the augmented group than the control group (7.3° ± 3.5° vs. 20.1° ± 5.4°). The augmented group had less (P < 0.001) implant failure [0% (n=0) vs. 23.8% (n=10)] for the control group) and more patients (P < 0.001) with no pain or minimal or occasional pain (Grade P1 or P2) than the control group [90.0% (n=81) vs. 66.7% (n=28)]. All patients in the augmented group and 39 (92.8%) patients in the control group experienced neurological recovery to Frankel Grade E. Three patients in the control group had improvement to Frankel Grade D from Frankel Grade C, but later had deterioration to Frankel Grade C because of loosening and dislodgement of the implant. Conclusion: Posterior body reconstruction with TpBA can maintain kyphosis correction and vertebral restoration, prevent implant failure and lead to better clinical results.