KPT-330, analog of KPT-185, is an orally bioavailable selective CRM1 inhibitor.IC50 value: Target: CRM1in vitro: As the clinical candidate analog of KPT-185, KPT-330 exhibits similar effects on the viability of T-ALL cells and elicits rapid apoptotic response. KPT-330 also reduces cell growth in MOLT-4, Jurkat, HBP-ALL, KOPTK-1, SKW-3, and DND-41 cell lines, with IC50 values of 34-203 nM [1]. in vivo: KPT-330 dramatically suppresses the growth of T-ALL cells (MOLT-4) and AML cells (MV4–11) in vivo, with little toxicity to normal haematopoietic cells [1]. In SCID mice with diffuse human MM bone lesions, KPT-330 inhibits MM-induced bone lysis and prolongs survival. Moreover, KPT-330 directly impairs osteoclastogenesis and bone resorption by blocking RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs [2].
PKF050-638 is a potent and selective inhibitor of HIV-1 Rev (IC50=0.04 μM). PKF050-638 inhibits the CRM1-mediated Rev nuclear export by disrupting CRM1-NES interaction[1].
KPT-276, analog of KPT-185, is an orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of CRM1.IC50 value:Target: CRM1in vitro: A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway [1]. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome [3].in vivo: One week after leukemic cell inoculation, the mice were given KPT-276 at 150 mg/kg via oral gavage, 3 times a week, or vehicle control. KPT-276 has the identical CRM1 binding warhead and specificity as KPT-185, similar biologic activity in vitro, but superior oral bioavailability and pharmacokinetics, which allow it to be used in vivo. Mice were monitored for survival. Some mice were killed at day 21 to assess the effects of KPT-276 on leukemia burden by measuring spleen weight and white blood cell count [2]. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity [3].
KPT-8602 Z-isomer is the less active isomer of KPT-8602. KPT-8602 is a potent CRM1 inhibitor.IC50：In Vitro: KPT 8602 Z-isomer exhibits different inhibitory effects on Z138, MM15, 3T3 cell lines, with IC50s of 100 nM-50 μM, < 100 nM, > 30 μM, respectively[1]. In Vivo:
Leptomycin A, a Streptomyces metabolite, is an inhibitor of CRM1 (exportin 1) that blocks CRM1 interaction with nuclear export signals, preventing the nuclear export of a broad range of proteins. Leptomycin A suppresses HIV-1 replication. Less potent than Leptomycin B[1][2].
Leptomycin B (CI 940; LMB) is a potent inhibitor of the nuclear export of proteins. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue. Leptomycin B is a potent antifungal antibiotic blocking the eukaryotic cell cycle[1].
KPT-251 is an orally active chromosome region maintenance 1 protein (CRM1) inhibitor. KPT-251 induces cancer cell apoptosis and shows antileukemic activity[1][2].
CBS9106 (SL-801) is a reversible oral CRM1 inhibitor with CRM1 degrading and antitumor activities[1].
LFS-1107 is a reversible CRM1 inhibitor (Kd: 12.5 pM). LFS-1107 can selectively eliminate extranodal natural killer/T cell lymphoma (ENKTL) cells and can be used for cancer research[1].
Verdinexor(KPT-335) is a novel, orally bioavailable selective inhibitor of nuclear export (SINE), inhibits nuclear export protein Exportin 1(XPO1/CRM1) against canine tumor cell lines; also reduce influenza virus replication in vitro and in vivo.IC50 value:Target: SINE; XPO1/CRM1in vitro: potently and selectively inhibit vRNP export and effectively inhibited the replication of various influenza virus A and B strains in vitro, including pandemic H1N1 virus, highly pathogenic H5N1 avian influenza virus, and the recently emerged H7N9 strain [1]. KPT-335 inhibited proliferation, blocked colony formation, and induced apoptosis of treated cells at biologically relevant concentrations of drug. Additionally, KPT-335 downregulated XPO1 protein while inducing a concomitant increase in XPO1 messenger RNA. Lastly, KPT-335 treatment of cell lines upregulated the expression of both protein and mRNA for the tumor suppressor proteins p53 and p21, and promoted their nuclear localization [3].in vivo: Prophylactic and therapeutic administration of verdinexor protected mice against disease pathology following a challenge with influenza virus A/California/04/09 or A/Philippines/2/82-X79, as well as reduced lung viral loads and proinflammatory cytokine expression, while having minimal toxicity [1]. A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities [2]. Inhibition of XPO1 with KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1v/v [4].
KPT-185 is an orally bioavailable selective inhibitor of CRM1 amd displayes potent antiproliferative properties at submicromolar concentrations (IC50 values:100-500nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts.IC50 value: 100-500 nM (AML cell lines) [1]Target: CRM1in vitro: Submicromolar concentrations of KPT-185 inhibited leukemia cell proliferation, with IC50 values ranging from 100nM to 500nM (MV4-11, Kasumi-1, OCI/AML3, MOLM-13, KG1a, and THP-1). KPT-185 at the predetermined IC50 value induced cell-cycle arrest at G1 with respect to vehicle-treated-control (DMSO) in MV4-11 (82.2% ± 3.69% vs 71.55% ± 0.21%, P < .01), OCI/AML3 (83.05% ± 6.84% vs 55.1% ± 2.26%, P < .01), and MOLM-13 (82.72% ± 1.14% vs 57.55 ± 3.46%, P < .01) cells at 24 hours. A significant accumulation of p53 in the nucleus of MV4-11 and OCI-AML3 was observed after treatment with KPT-185 [1]. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome [2]. in vivo: In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition [3].
KPT-8602 is a second-generation exportin-1 inhibitor, shows similar in vitro potency compared with KPT-330.In vitro: KPT-8602 induces caspase-dependent apoptosis in a panel of leukemic cell lines in vitro. Using CRISPR/Cas9 genome editing we demonstrats the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validats the drug target interaction. [1]In vivo: KPT-8602 shows potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.[1]