br Clinical trials of CRM inhibitors KPT clinical
Clinical trials of CRM1 inhibitors KPT-330 clinical trials have been initiated with promising very early results. One trial includes patients with advanced solid tumors whose disease has progressed after at least one prior therapy for metastatic disease (NCT01607905). Another trial includes patients with advanced hematological malignancies including CLL, non-Hodgkin lymphoma, MM, and Waldenstrom macroglobulinaemia whose disease has relapsed after standard therapies (NCT01607892). Yet another phase IB trial includes patients whose soft tissue or bone sarcomas relapsed, or are progressing, with at least one prior therapy for metastatic disease (NCT01896505). Patients with AML have been also eligible very recently in four on-going clinical trials (NCT02091245, NCT01607892, NCT02088541, NCT02093403), and the trials including patients with glioblastoma or gynecologic malignancies have also been initiated (ClinicalTrials.gov). Early responses include complete remissions in large cell lymphomas, chronic lymphocytic leukemias (Kuruvilla et al., 2013), and AMLs (Savona et al., 2013), which promoted a trial in dogs developing lymphomas (London et al., 2014), and several combination trials. It is obviously too early to assess the full clinical potential of these agents, but the early responses in highly chemo-refractory patients are encouraging. Side effects include anorexia, fatigue, weight loss and gastrointestinal symptoms, which can be substantial (London et al., 2014).
Conclusion and future perspectives
Conflict of interest
Acknowledgments This work was supported in part by grants from the National Institutes of Health (CA49639, 100632, CA136411, and CA16672), the Paul and Mary Haas Chair in Genetics (all to M.A.), and the Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad Award (to J. I.)
Introduction In contrast to prokaryotic cells, eukaryotic Amodiaquine dihydrochloride dihydrate reveal a high degree of spatial compartmentalization into membrane-engulfed entities. This, for instance, enables a strict spatiotemporal separation of cellular processes such as transcription, occurring in the nucleus, and translation in the cytoplasm. Transport between the nucleus and the cytoplasm proceeds through nuclear pore complexes (NPC) and depends on specialized transport systems. Macromolecules exceeding 30–40 kDa require the aid of karyopherins (KAPs) as mediators to pass the NPC efficiently (Chook and Süel, 2011, Cook and Conti, 2010). The majority of KAPs are members of a superfamily named after Importin-β (Impβ), the first receptor identified (Görlich et al., 1997, Radu et al., 1995). They are divided into importins and exportins according to the direction of cargo transport. Their common biochemical properties are the capability to interact with the NPC and bind to the small GTPase Ran (Ras-related nuclear antigen). The asymmetric distribution of the Ran-regulating factors with the Ran guanine-nucleotide exchange factor (RanGEF) residing in the nucleus and the Ran GTPase activating protein (RanGAP) located in the cytoplasmic compartment ensures that nuclear Ran predominantly occurs in its GTP-bound form. In contrast to the cytoplasmic, GDP-bound form of Ran, RanGTP can bind to KAPs. RanGTP binding modulates the affinity of KAPs for cargo and thereby enforces directionality of transport. On a structural level, all members of the Impβ superfamily share a common arrangement of about 20 building blocks, so-called HEAT repeats (Kobe et al., 1999), each consisting of two antiparallel α helices connected by a loop. Their consecutive arrangement results in an overall superhelical shape resembling a solenoid (Fontes et al., 2000). In exportins, RanGTP promotes cargo binding predominantly by interacting simultaneously with receptor and cargo, as for instance seen in Exportin-t, Exportin5, or Cse1p/CAS (Cook et al., 2005, Cook et al., 2009, Matsuura and Stewart, 2004, Okada et al., 2009). In contrast, the export receptor CRM1 (chromosome region maintenance 1), which recognizes the majority of proteins destined for export (Hutten and Kehlenbach, 2007), displays no direct interaction of Ran and cargo. CRM1 in the cargo-bound state exhibits a toroidal, compact, shape with the N- and C-terminal HEAT repeats in close contact (Koyama and Matsuura, 2010, Monecke et al., 2009). A coexisting less compact but still toroidal shape has been described during some states of its transport cycle (Dong et al., 2009b; Figure 1A). Recent structural analysis of free CRM1 from Chaetomium thermophilum (ctCRM1) and Saccharomyces cerevisiae (scCRM1) revealed that, in these organisms, CRM1 also adopts a more or less extended superhelical shape without close interaction of the N- and C-terminal regions (Monecke et al., 2013, Saito and Matsuura, 2013).