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Natick, MA, United States

Kalid O.,Karyopharm Therapeutics
Journal of computer-aided molecular design | Year: 2012

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

DESCRIPTION provided by applicant Systemic lupus erythematosus SLE is a complex autoimmune disease with a broad spectrum of clinical manifestations affecting several organs and associated with dysregulation of the immune system This disease affects millions of individuals with women and underserved minorities disproportionately burdened It is associated with significant morbidity and mortality yet treatment approaches remain broadly immunosuppressive anti inflammatory or palliative Despite the considerable progress on understanding SLE immune pathogenesis only one drug has been approved for the treatment of lupus patients in the last years emphasizing the urgent need for novel therapies Considering the central role of auto antibodies in the amplification of auto immunity a goal in lupus therapy is the elimination of auto reactive antibody secreting cells ASC Karyopharm Therapeutics has pioneered the development of Selective Inhibitors of Nuclear Export SINE compounds and wishes to investigate their potential utility in auto immune diseases In collaboration with the Anolik laboratory at the University of Rochester Medical Center we will evaluate a novel approach to the treatment of autoimmune disease that targets the generation and survival of autoreactive plasma cells PCs via inhibition of nuclear export SINE compounds have a potent effect on the generation of splenic T follicular helper cells TFH and germinal center GC B cells and selectively inhibit production of auto reactive ASCs specific for double stranded DNA SINEs had a compelling effect on GC formation stability prevented expansion of memory TFH and B cells and markedly reduced mRNA expression of molecules critical for survival and recruitment of auto reactive ASC including certain cytokines interleukin and interferon induced chemokines Thus SINE drugs strongly and selectively ablated auto reactive PCs by targeting pathways that are critical for their generation and survival recruitment into inflamed kidneys In the proposed project we will define the efficacy of SINE compounds in SLE in order to accelerate the translation of these novel compounds into lupus clinical trials In Aim we will identify the optimal treatment strategy of SINE compounds in murine SLE model by i refining the dose and time required for GCs and PCs to exhibit a response in vivo ii optimizing the induction treatment strategy and iii determining the duration of SINE compound effect and define the need for maintenance therapy In Aim we will examine the protective immunity effects of the SINE compounds by i evaluating the immune responses in murine SLE during treatment and ii determining the recovery of protective immune responses after cessation of therapy Successful completion of these studies will lead to a Phase II proposal to move SINE compounds into extensive preclinical safety testing in preparation for clinical trials The goal is to develop an efficacious dosing strategy using a novel treatment approach that targets key synergistic pathways in SLE disease pathogenesis with the long term goal of delivering an improved therapy for SLE and other autoimmune diseases PUBLIC HEALTH RELEVANCE Systemic Systemic lupus erythematosus SLE is a complex autoimmune disease affecting multiple organs and with limited treatment options We seek to investigate the potential utility of Selective Inhibitors of Nuclear Export SINE compounds in auto immune diseases like SLE


Patent
Karyopharm Therapeutics | Date: 2014-03-19

The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by structural formula I: or a pharmaceutically acceptable salt thereof, wherein the values and alternative values for the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.


Patent
Karyopharm Therapeutics | Date: 2015-06-10

The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by structural formula I: or a pharmaceutically acceptable salt thereof, wherein the values and alternative values for the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.


Patent
Karyopharm Therapeutics | Date: 2013-06-28

The invention generally relates to the field of nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to new substituted-heterocyclic azole compounds, the synthesis and use of these compounds and their pharmaceutical compositions, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity such as in treating cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth and fibrosis including cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and other renal disorders, and for the treatment of viral infections (both acute and chronic).

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