- Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction
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Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
- Aguilar, Angelo,Zheng, Ke,Xu, Tianfeng,Xu, Shilin,Huang, Liyue,Fernandez-Salas, Ester,Liu, Liu,Bernard, Denzil,Harvey, Kaitlin P.,Foster, Caroline,McEachern, Donna,Stuckey, Jeanne,Chinnaswamy, Krishnapriya,Delproposto, James,Kampf, Jeff W.,Wang, Shaomeng
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p. 6015 - 6034
(2019/07/03)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
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The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
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Paragraph 00787; 00788; 00789; 00790; 001600; 001601; 001602
(2019/01/10)
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- CHIRAL DIARYL MACROCYCLES AS MODULATORS OF PROTEIN KINASES
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The present disclosure relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
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Paragraph 0528
(2017/01/23)
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- PIPERIDINES AS MENIN INHIBITORS
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The present disclosure provides compounds represented by Formula (I): (Formula(I)) and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R2, R3a, R3b, A, G, X, and Y are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I) for use to treat a condition or disorder responsive to menin inhibition such as cancer.
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Paragraph 0424; 0425
(2017/12/13)
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- Copper-Catalyzed Asymmetric Borylative Ring Opening of Diazabicycles
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Highly enantioselective, copper-catalyzed ring opening of bicyclic hydrazines using a diboron reagent was accomplished with (R,R)-taniaphos as a chiral ligand. Desymmetrization of various bicyclic hydrazines by boryl substitution afforded 3-Bpin-4-hydrazino-cyclopentene derivatives with enantioselectivity up to >99% under mild conditions. The resulting allylic boron products were utilized in further organic transformations. Kinetic resolution of a racemic bicyclic oxazine gave useful information about the relative rates of C-O and C-N bond cleavage.
- Lee, Hyesu,Han, Jung Tae,Yun, Jaesook
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p. 6487 - 6490
(2016/10/14)
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- IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
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The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
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Paragraph 0190-0191
(2015/02/25)
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- Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core
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New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (～2 to 50 nM), MMP-13 (～2 to 50 nM), and MMP-14 (～4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ～850 to >50 000 nM; MMP-7, ～4000 to >25 000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease.
- Jin, Yonghao,Roycik, Mark D.,Bosco, Dale B.,Cao, Qiang,Constantino, Manuel H.,Schwartz, Martin A.,Sang, Qing-Xiang Amy
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p. 4357 - 4373
(2013/07/19)
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- SELECTIVE ANDROGEN RECEPTOR MODULATORS
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The present invention provides novel selective androgen receptor modulators and their salts and pharmaceutical compositions thereof.
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- SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa
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In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiam
- Qiao, Jennifer X.,Chang, Chong-Hwan,Cheney, Daniel L.,Morin, Paul E.,Wang, Gren Z.,King, Sarah R.,Wang, Tammy C.,Rendina, Alan R.,Luettgen, Joseph M.,Knabb, Robert M.,Wexler, Ruth R.,Lam, Patrick Y.S.
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p. 4419 - 4427
(2008/02/10)
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- CYCLIC DIAMINES AND DERIVATIVES AS FACTOR XA INHIBITORS
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The present application describes cyclic diamino compounds, derivatives thereof, and pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.
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- (1S,2R/1R,2S)-cis-cyclopentyl PNAs (cpPNAs) as constrained PNA analogues: Synthesis and evaluation of aeg-cpPNA chimera and stereopreferences in hybridization with DNA/RNA
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Conformationally constrained chiral PNA analogues were designed on the basis of stereospecific imposition of a 1,2-cis-cyclopentyl moiety on an aminoethyl segment of aegPNA. It is known that the cyclopentane ring is a relatively flexible system in which the characteristic puckering dictates the pseudoaxial/pseudoequatorial dispositions of substituents. Hence, favorable torsional adjustments are possible to attain the necessary hybridization- competent conformations when the moiety is imposed on the conventional PNA backbone. The synthesis of the enantiomerically pure 1,2-cis-cyclopentyl PNA monomers (10a and 10b) was achieved by stereoselective enzymatic hydrolysis of a key intermediate ester 2. The chiral (1S,2R/1R,2S)-aminocyclopentylglycyl thymine monomers were incorporated into PNA oligomers at defined positions and through the entire sequence. Hybridization studies with complementary DNA and RNA sequences using UV-Tm measurements indicate that aeg-cpPNA. chimera form thermally more stable complexes than aegPNA with stereochemistry-dependent selective binding of cDNA/RNA. Differential gel shift retardation was observed on hybridization of aeg-cpPNAs with complementary DNA.
- Govindaraju,Kumar, Vaijayanti A.,Ganesh, Krishna N.
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p. 5725 - 5734
(2007/10/03)
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- cis-Cyclopentyl PNA (cpPNA) as constrained chiral PNA analogues: stereochemical dependence of DNA/RNA hybridization.
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DNA/RNA hybridization studies of PNA-T oligomers with cis-(1S,2R/1R,2S)-cyclopentyl units in the backbone show stereochemistry dependent binding with RNA/DNA discrimination.
- Govindaraju,Kumar, Vaijayanti A,Ganesh, Krishna N
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p. 860 - 861
(2007/10/03)
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- LACTAM-CONTAINING CYCLIC DIAMINES AND DERIVATIVES AS FACTOR XA INHIBITORS
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The present application describes lactam-containing cyclic diamines and derivatives thereof of Formula I: or pharmaceutically acceptable salt forms thereof, wherein M is a non-aromatic carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trysin-like serine proteases, specifically factor Xa.
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Page/Page column 98
(2010/02/08)
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- 1,1-DISUBSTITUTED CYCLOALKYL DERIVATIVES AS FACTOR XA INHIBITORS
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The present application describes 1,1-disubstituted cycloalkyl compounds and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.
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- Synthesis of enantiopure N-tert-butoxycarbonyl-2-aminocycloalkanones
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A route to enantiomerically pure N-tert-butoxycarbonyl-2-aminocycloalkanones (ring size: 5-8 membered) from the corresponding cycloalkene oxides is described. The procedure involves (1) aminolysis with (S)-α-methylbenzylamine/Me3Al and chromatographic separation of diastereomers, (2) hydrogenolysis to afford the trans-2-aminocycloalkanols, (3) tert-butoxycarbonyl (Boc) protection, and (4) PCC oxidation.
- Aube,Wolfe,Yantiss,Cook,Takusagawa
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p. 3003 - 3012
(2007/10/02)
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