- Discovery of novel and orally bioavailable CDK 4/6 inhibitors with high kinome selectivity, low toxicity and long-acting stability for the treatment of multiple myeloma
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Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.
- Yuan, Kai,Kuang, Wenbin,Chen, Weijiao,Ji, Minghui,Min, Wenjian,Zhu, Yasheng,Hou, Yi,Wang, Xiao,Li, Jiaxing,Wang, Liping,Yang, Peng
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- INDOLE COMPOUNDS AS ANDROGEN RECEPTOR MODULATORS
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Provided herein are compounds of formula (V) that bind to BF3 of an androgen receptor (AR), which can modulate the AR for the treatment of Kennedy's disease.
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- Five-membered heterocyclic oxo carboxylic acid compound and medical application thereof
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The invention relates to a five-membered heterocyclic oxo carboxylic acid compound and a medical application thereof. Specifically, the invention relates to a compound, a pharmaceutical salt, a prodrug, a hydrate, a solvate or a crystal form as shown in a formula (I), and also relates to a preparation method of the compound, a pharmaceutical composition containing the compound and an application of the pharmaceutical composition as a secretion regulator of interferon type I, especially as an STING agonist in preparation of medicines for preventing and/or treating I-type interferon related diseases.
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Paragraph 0655-0659
(2021/05/01)
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- Azaindole pyrimidinamine heterocyclic compound as well as preparation method and application thereof
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The invention discloses an azaindole pyrimidinamine heterocyclic compound as well as a preparation method and application thereof. The compound is shown as a formula (S). The compound provided by the invention can inhibit malignant proliferation of cancers, has good treatment effect, low toxicity and good drug metabolism characteristics, is not easy to generate drug resistance, and can be used for preparing drugs for treating cancers or tumor-related diseases. The cancers or tumor-related diseases include multiple myeloma, leukemia, breast cancer, prostate cancer, lung cancer, liver cancer, gastric cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer and endometrial cancer.
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- TYK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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- Novel meriolin derivatives as rapid apoptosis inducers
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3-(Hetero)aryl substituted 7-azaindoles possessing multikinase inhibitor activity are readily accessed in a one-pot Masuda borylation-Suzuki coupling sequence. Several promising derivatives were identified as apoptosis inducers and, emphasizing the multik
- Drie?en, Daniel,Stuhldreier, Fabian,Frank, Annika,Stark, Holger,Wesselborg, Sebastian,Stork, Bj?rn,Müller, Thomas J.J.
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p. 3463 - 3468
(2019/06/27)
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- Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent in Vitro and in Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
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In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ～33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.
- Singh, Umed,Chashoo, Gousia,Khan, Sameer U.,Mahajan, Priya,Nargotra, Amit,Mahajan, Girish,Singh, Amarinder,Sharma, Anjna,Mintoo, Mubashir J.,Guru, Santosh Kumar,Aruri, Hariprasad,Thatikonda, Thanusha,Sahu, Promod,Chibber, Pankaj,Kumar, Vikas,Mir, Sameer A.,Bharate, Sonali S.,Madishetti, Sreedhar,Nandi, Utpal,Singh, Gurdarshan,Mondhe, Dilip Manikrao,Bhushan, Shashi,Malik, Fayaz,Mignani, Serge,Vishwakarma, Ram A.,Singh, Parvinder Pal
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p. 9470 - 9489
(2017/12/26)
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- Iridium-catalyzed C-H borylation of heteroarenes: Scope, regioselectivity, application to late-stage functionalization, and mechanism
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A study on the iridium-catalyzed C-H borylation of heteroarenes is reported. Several heteroarenes containing multiple heteroatoms were found to be amenable to C-H borylation catalyzed by the combination of an iridium(I) precursor and tetramethylphenanthroline. The investigations of the scope of the reaction led to the development of powerful rules for predicting the regioselectivity of borylation, foremost of which is that borylation occurs distal to nitrogen atoms. One-pot functionalizations are reported of the heteroaryl boronate esters formed in situ, demonstrating the usefulness of the reported methodology for the synthesis of complex heteroaryl structures. Application of this methodology to the synthesis and late-stage functionalization of biologically active compounds is also demonstrated. Mechanistic studies show that basic heteroarenes can bind to the catalyst and alter the resting state from the olefin-bound complex observed during arene borylation to a species containing a bound heteroarene, leading to catalyst deactivation. Studies on the origins of the observed regioselectivity show that borylation occurs distal to N-H bonds due to rapid N-H borylation, creating an unfavorable steric environment for borylation adjacent to these bonds. Computational studies and mechanistic studies show that the lack of observable borylation of C-H bonds adjacent to basic nitrogen is not the result of coordination to a bulky Lewis acid prior to C-H activation, but the combination of a higher-energy pathway for the borylation of these bonds relative to other C-H bonds and the instability of the products formed from borylation adjacent to basic nitrogen.
- Larsen, Matthew A.,Hartwig, John F.
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supporting information
p. 4287 - 4299
(2014/04/03)
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- Rapid preparation of triazolyl substituted NH-heterocyclic kinase inhibitors via one-pot Sonogashira coupling-TMS-deprotection-CuAAC sequence
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The one-pot, three-component Sonogashira coupling-TMS-deprotection-CuAAC ("click") sequence is the key reaction for the rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, and imidazole. Subsequently, the protective group was readily removed to give the corresponding triazolyl derivatives of these tremendously important NH-heterocycles. All compounds have been tested in a broad panel of kinase assays. Several compounds, 8f, 8h, 8k, and 8l, have been shown to inhibit the kinase PDK1, a target with high oncology relevance, and thus they are promising lead structures for the development of more active derivatives. The X-ray structure analysis of compound 8f in complex with PDK1 has revealed the detailed binding mode of the molecule in the kinase. The Royal Society of Chemistry 2011.
- Merkul, Eugen,Klukas, Fabian,Dorsch, Dieter,Graedler, Ulrich,Greiner, Hartmut E.,Mueller, Thomas J. J.
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p. 5129 - 5136
(2011/09/13)
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- Rapid synthesis of bis(hetero)aryls by one-pot Masuda borylation-Suzuki coupling sequence and its application to concise total syntheses of meridianins A and G
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3-(Hetero)aryl substituted indoles, 7-azaindoles, and pyrroles can be obtained in a very concise fashion via a one-pot Masuda borylation-Suzuki coupling sequence. The concise total syntheses of the marine natural products meridianins A (5) and G (4i) nice
- Merkul, Eugen,Schaefer, Elisabeth,Mueller, Thomas J. J.
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supporting information; experimental part
p. 3139 - 3141
(2011/06/28)
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- One-pot synthesis of diazine-bridged bisindoles and concise synthesis of the marine alkaloid hyrtinadine A
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Diazine-bridged bisindoles are readily obtained from N-Bocprotected 3-iodoindoles and 3-iodo-7-azaindole in a pseudo three-component reaction involving a one-pot Masuda borylation-Suzuki arylation sequence. Some of the title com-pounds display promising c
- Tasch, Boris O. A.,Merkul, Eugen,Mueller, Thomas J. J.
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supporting information; experimental part
p. 4532 - 4535
(2011/10/03)
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- Boc groups as protectors and directors for ir-catalyzed C-H borylation of heterocycles
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(Chemical Equation Presented) Ir-catalyzed C-H borylation is found to be compatible with Boc protecting groups. Thus, pyrroles, indoles, and azaindoles can be selectively functionalized at C-H positions β to N. The Boc group can be removed on thermolysis
- Kallepalli, Venkata A.,Shi, Feng,Paul, Sulagna,Onyeozili, Edith N.,Maleczka Jr., Robert E.,Smith III, Milton R.
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supporting information; experimental part
p. 9199 - 9201
(2010/03/02)
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- ANTIBACTERIAL CONDENSED THIAZOLES
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Compound of formula (I) have antibacterial activity: wherein: m is 0 or 1; Q is hydrogen or cyclopropyl; AIk - is an optionally substituted, divalent C1-C6 alkylene, alkenylene or alkynylene radical which may contain an ether (-0-), thioether (-S-) or amino (-NR)- link, wherein R is hydrogen, -CN or C1-C3 alky!; X is -C(=O)NR6-, or -C(=O)O- wherein R6 is hydrogen, optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; Z1 is -N= or -CH= Z2 is -N= or -C(R1)=; R1 is hydrogen, methyl, ethyl, ethenyl, ethynyl, methoxy, mercapto, mercaptomethyl halo, fully or partially fluorinated (C1-C2)alkyl, (C1-C2JaIkOXy or (C1-C2)alkylthio, nitro, or nitrile (-CN); R2 is a group Q1 -[Alk1]q-Q2 -, wherein q is 0 or 1; AIkl is an optionally substituted, divalent, straight chain or branched C1-C6 alkylene, or C2-C6 alkenylene or C2-C6 alkynylene radical which may contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR)- link; Q2 is an optionally substituted divalent monocyclic carbocyclic or heterocyclic radical having 5 or 6 ring atoms or an optionally substituted divalent bicyclic carbocyclic or heterocyclic radical having 9 or 10 ring atoms; Q1 is hydrogen, an optional substituent or an optionally substituted carbocyclic or heterocyclic radical having 3-7 ring atoms
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Page/Page column 59; 60
(2009/07/17)
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- PYRIDINONYL PDK1 INHIBITORS
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The present invention provides pyridinonyl PDKl inhibitors and methods of treating cancer using the same.
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Page/Page column 101; 109
(2008/06/13)
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