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1.
J Med Chem ; 62(8): 3971-3988, 2019 04 25.
Article in English | MEDLINE | ID: mdl-30929420

ABSTRACT

Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.


Subject(s)
Antineoplastic Agents/chemistry , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Small Molecule Libraries/chemistry , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Azepines/chemistry , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Female , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Dynamics Simulation , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Protein Structure, Tertiary , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship , Xenograft Model Antitumor Assays
2.
Bioorg Med Chem Lett ; 29(6): 786-790, 2019 03 15.
Article in English | MEDLINE | ID: mdl-30728114

ABSTRACT

The PD-1 immune checkpoint pathway is a highly validated target for cancer immunotherapy. Despite the potential advantages of small molecule inhibitors over antibodies, the discovery of small molecule checkpoint inhibitors has lagged behind. To discover small molecule inhibitors of the PD-1 pathway, we have utilized a fragment-based approach. Small molecules were identified that bind to PD-L1 and crystal structures of these compounds bound to PD-L1 were obtained.


Subject(s)
B7-H1 Antigen/metabolism , Small Molecule Libraries/metabolism , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/chemistry , Crystallography, X-Ray , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Protein Binding , Small Molecule Libraries/chemistry
3.
J Med Chem ; 61(6): 2410-2421, 2018 03 22.
Article in English | MEDLINE | ID: mdl-29323899

ABSTRACT

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.


Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Apoptosis , Caspases/metabolism , Cell Division/drug effects , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Enzyme Activators/chemical synthesis , Enzyme Activators/pharmacology , Humans , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Structure-Activity Relationship
4.
Protein Expr Purif ; 102: 69-75, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25131858

ABSTRACT

Recombinant human mast cell chymase (rhChymase) was expressed in secreted form as an active enzyme in the SuperMan5 strain of GlycoSwitch® Pichia pastoris, which is engineered to produce proteins with (Man)5(GlcNAc)2 Asn-linked glycans. Cation exchange and heparin affinity chromatography yielded 5mg of active rhChymase per liter of fermentation medium. Purified rhChymase migrated on SDS-PAGE as a single band of 30 kDa and treatment with peptide N-glycosidase F decreased this to 25 kDa, consistent with the established properties of native human chymase (hChymase). Polyclonal antibodies against hChymase detected rhChymase by Western blot. Active site titration with Eglin C, a potent chymase inhibitor, quantified the concentration of purified active enzyme. Kinetic analyses with succinyl-Ala-Ala-Pro-Phe (suc-AAPF) p-nitroanilide and thiobenzyl ester synthetic substrates showed that heparin significantly reduced KM, whereas heparin effects on kcat were minor. Pure rhChymase with Asn-linked glycans closely resembles hChymase. This bioengineering approach avoided hyperglycosylation and provides a source of active rhChymase for other studies as well as a foundation for production of recombinant enzyme with human glycosylation patterns.


Subject(s)
Chymases/genetics , Mast Cells/enzymology , Pichia/genetics , Cell Engineering , Chymases/chemistry , Chymases/isolation & purification , Chymases/metabolism , Cloning, Molecular , Fermentation , Glycosylation , Humans , Pichia/physiology , Polysaccharides/chemistry , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism
5.
Environ Sci Technol ; 36(2): 254-62, 2002 Jan 15.
Article in English | MEDLINE | ID: mdl-11827060

ABSTRACT

In this study, dissolved Kr and SF6 gases were used to determine various hydrogeological parameters of laboratory columns under water-saturated and partially saturated conditions as a function of the flow velocity. The dissolved gases behaved conservatively in saturated columns but were significantly retarded in unsaturated conditions as a direct function of the Henry's law constant (KH) and the ratio of column pore spaces filled with air and water (Vg/Vw). Lower aqueous diffusion coefficients for SF6 compared to that for Kr also resulted in significant rate-limited mass transport across gas-water interface. This effect was exacerbated at higher flow velocities as was indicated by the asymmetric shape of breakthrough curves, more so in the case of SF6. A nonequilibrium advective-dispersive transport model accurately described tracer breakthrough and was used to estimate parameters such as final Vg/Vw under partially saturated conditions and partitioning rates. Internally consistent model results were obtained for both dissolved gases despite the wide range in physical properties (e.g., KH and aqueous diffusion coefficients), suggesting that dissolved Kr and SF6 may be used in conjunction to delineate and validate aquifer characteristics simultaneously from a single pulse injection of the tracer.


Subject(s)
Soil Pollutants/analysis , Water Pollutants/analysis , Water Supply , Geological Phenomena , Geology , Krypton/analysis , Models, Chemical , Solubility , Sulfur Hexafluoride/analysis , Water Movements
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