The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia

Vercruysse, Thomas; Bie, Jolien De; Neggers, Jasper E.; Jacquemyn, Maarten; Vanstreels, Els; Schmid-Burgk, Jonathan L.; Hornung, Veit; Baloglu, Erkan; Landesman, Yosef; Senapedis, William; Shacham, Sharon; Dagklis, Antonis; Cools, Jan; Daelemans, Dirk

doi:10.1158/1078-0432.ccr-16-1580

Cited by 57 publications

(60 citation statements)

References 25 publications

(29 reference statements)

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“…The many available NES structures, diversity of NES conformations and the structurally conserved one-turn helix NES element revealed here will enable development of structure- rather than sequence-based NES predictors (Raveh et al, 2011; Schindler et al, 2015; Trellet et al, 2013; Yan et al, 2016). There is a need to identify many more CRM1 cargoes as apoptosis of different cancer cells upon CRM1 inhibition by the drug Selinexor (in clinical trials for a variety of cancers) and other inhibitors (Parikh et al, 2014; Mendonca et al, 2014; Das et al, 2015; Alexander et al, 2016; Gounder et al, 2016; Abdul Razak et al, 2016; Lapalombella et al, 2012; Inoue et al, 2013; Etchin et al, 2013; Tai et al, 2014; Cheng et al, 2014; Kim et al, 2016; Hing et al, 2016; Vercruysse et al, 2016) appears to be driven by nuclear accumulation of different sets of NES-containing cargoes, but identities of most of these apoptosis-causing cargoes are still unknown.…”

Section: Discussionmentioning

confidence: 99%

Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

Fung

Chook

2017

eLife

100

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Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.DOI: http://dx.doi.org/10.7554/eLife.23961.001

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Section: Discussionmentioning

confidence: 99%

Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

Fung

Chook

2017

eLife

100

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“…Genome-edited HAP1 cell lines were generated using the CRISPaint principle [50] and similarly as described before [51]. Briefly, cells were transfected using TurboFectin 8.0 (Origene) according to the manufacturer's instructions with a plasmid encoding an sgRNA targeting the C-terminus of XPO1 (5 0 -GAGAGAAATAGCCCTACGGC-3 0 ), a plasmid encoding SpCas9 and an sgRNA targeting the donor plasmid (5 0 -GCCAGTACCCAAAAAGCGCC-3 0 ), and a repair donor plasmid.…”

Section: Crispr/cas9 Genome Editing Dna Extraction and Sequencingmentioning

confidence: 99%

STK 38 kinase acts as XPO 1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes

et al. 2019

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STK38 (also known as NDR1) is a Hippo pathway serine/threonine protein kinase with multifarious functions in normal and cancer cells. Using a context‐dependent proximity‐labeling assay, we identify more than 250 partners of STK38 and find that STK38 modulates its partnership depending on the cellular context by increasing its association with cytoplasmic proteins upon nutrient starvation‐induced autophagy and with nuclear ones during ECM detachment. We show that STK38 shuttles between the nucleus and the cytoplasm and that its nuclear exit depends on both XPO1 (aka exportin‐1, CRM1) and STK38 kinase activity. We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit. We expand our model to other cellular contexts by discovering that XPO1 phosphorylation by STK38 regulates also the nuclear exit of Beclin1 and YAP1, key regulator of autophagy and transcriptional effector, respectively. Collectively, our results reveal STK38 as an activator of XPO1, behaving as a gatekeeper of nuclear export. These observations establish a novel mechanism of XPO1‐dependent cargo export regulation by phosphorylation of XPO1's C‐terminal auto‐inhibitory domain.

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“…The most likely mechanism of KPT-330 in Ph+ ALL was the nuclear accumulation of SET and CIP2A and restoration of various tumor suppressors such as PP2A, p53, p21, and FOXO3a [40] . KPT-8602 showed potent anti-leukemic activity against T-ALL mouse model as well as in two PDX ALL models [41] . Phase-I clinical trials were initiated using selinexor in combination with fludarabine and cytarabine for the pediatric patients with relapsed/refractory leukemia.…”

Section: Role Of Selective Inhibitors Of Nuclear Export (Xpo1 Inhibitmentioning

confidence: 99%

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

Sneha¹,

P²,

Bindhya³

et al. 2017

Can Cell Microenviron

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Cancer is one of the leading cause of morbidity and mortality worldwide. Regulated nucleo-cytoplasmic shuttling is very crucial for maintaining cellular homeostasis. Emerging evidence suggests that deregulation of the nucleo-cytoplasmic transport results in abnormal cell growth, cell cycle, apoptosis, tumor progression and drug resistance. Exportin-1 (also called as chromosome region maintenance 1) belongs to karyopherin-β superfamily and is the main mediator of nuclear export in several cell types. The XPO1/CRM1 protein is overexpressed in liposarcoma, Ewing sarcoma, ovarian carcinoma, pancreatic cancer, hepatocellular carcinoma, lung carcinoma, osteosarcoma, gastric carcinoma, melanoma, glioma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid/lymphoid leukemia as well as multiple myeloma. Hot spot mutations were observed in many cancers. Higher levels of XPO1/CRM1 are associated with poor prognosis, resistance to chemotherapy and recurrence in a large number of human malignancies. There are growing evidence that provided the foundation that inhibition of nuclear export by inhibiting nuclear export receptor (XPO1) might be a potential targeted therapeutic approach for the treatment of human cancers in the clinic. In the present review, we will discuss the role of XPO1 in cancers and potential of selective inhibitors of nuclear export (XPO1 inhibitors) to restore the normal function of tumor suppressor and growth regulatory proteins by blocking their export. Selinexor (KPT-330) is an orally available, highly potent and is being tested in human phase-I/II clinical trials in both haematological and solid malignancies.

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The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia

Cited by 57 publications

References 25 publications

Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

STK 38 kinase acts as XPO 1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

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