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Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

ABSTRACT: Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

SUBMITTER: Hartwell KA

PROVIDER: S-EPMC4009363 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

Hartwell Kimberly A KA Miller Peter G PG Mukherjee Siddhartha S Kahn Alissa R AR Stewart Alison L AL Logan David J DJ Negri Joseph M JM Duvet Mildred M Järås Marcus M Puram Rishi R Dancik Vlado V Al-Shahrour Fatima F Kindler Thomas T Tothova Zuzana Z Chattopadhyay Shrikanta S Hasaka Thomas T Narayan Rajiv R Dai Mingji M Huang Christina C Shterental Sebastian S Chu Lisa P LP Haydu J Erika JE Shieh Jae Hung JH Steensma David P DP Munoz Benito B Bittker Joshua A JA Shamji Alykhan F AF Clemons Paul A PA Tolliday Nicola J NJ Carpenter Anne E AE Gilliland D Gary DG Stern Andrew M AM Moore Malcolm A S MAS Scadden David T DT Schreiber Stuart L SL Ebert Benjamin L BL Golub Todd R TR

Nature chemical biology 20131027 12

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stro ...[more]

PMID: 24161946

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Project description:Target-specific scoring methods are more commonly used to identify small-molecule inhibitors among compounds docked to a target of interest. Top candidates that emerge from these methods have rarely been tested for activity and specificity across a family of proteins. In this study we docked a chemical library into CaMKII?, a member of the Ca2+ /calmodulin (CaM)-dependent protein kinase (CaMK) family, and re-scored the resulting protein-compound structures using Support Vector Machine SPecific (SVMSP), a target-specific method that we developed previously. Among the 35 selected candidates, three hits were identified, such as quinazoline compound 1 (KIN-1; N4-[7-chloro-2-[(E)-styryl]quinazolin-4-yl]-N1,N1-diethylpentane-1,4-diamine), which was found to inhibit CaMKII? kinase activity at single-digit micromolar IC50 . Activity across the kinome was assessed by profiling analogues of 1, namely 6 (KIN-236; N4-[7-chloro-2-[(E)-2-(2-chloro-4,5-dimethoxyphenyl)vinyl]quinazolin-4-yl]-N1,N1-diethylpentane-1,4-diamine), and an analogue of hit compound 2 (KIN-15; 2-[4-[(E)-[(5-bromobenzofuran-2-carbonyl)hydrazono]methyl]-2-chloro-6-methoxyphenoxy]acetic acid), namely 14 (KIN-332; N-[(E)-[4-(2-anilino-2-oxoethoxy)-3-chlorophenyl]methyleneamino]benzofuran-2-carboxamide), against 337 kinases. Interestingly, for compound 6, CaMKII? and homologue CaMKII? were among the top ten targets. Among the top 25 targets of 6, IC50 values ranged from 5 to 22??m. Compound 14 was found to be not specific toward CaMKII kinases, but it does inhibit two kinases with sub-micromolar IC50 values among the top 25. Derivatives of 1 were tested against several kinases including several members of the CaMK family. These data afforded a limited structure-activity relationship study. Molecular dynamics simulations with explicit solvent followed by end-point MM-GBSA free-energy calculations revealed strong engagement of specific residues within the ATP binding pocket, and also changes in the dynamics as a result of binding. This work suggests that target-specific scoring approaches such as SVMSP may hold promise for the identification of small-molecule kinase inhibitors that exhibit some level of specificity toward the target of interest across a large number of proteins.

Dataset Information

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

Publications

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

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