- From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4)
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The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAFV600E inhibitor PLX4032 (8). Applying an iterative multi-parameter optimization process we carved out essential structural features yielding in compounds with a low nanomolar affinity for MKK4 and excellent selectivity profiles against the main off-targets MKK7 and JNK1, which, upon relevant inhibition, would totally abrogate the pro-regenerative effect of MKK4 inhibition, as well as against the off-targets MAP4K5, ZAK and BRAF with selectivity factors ranging from 40 to 430 for our best-balanced compounds 70 and 73.
- Kl?vekorn, Philip,Pfaffenrot, Bent,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
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- Selective CRAF Inhibition Elicits Transactivation
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Discovering molecules that regulate closely related protein isoforms is challenging, and in many cases the consequences of isoform-specific pharmacological regulation remains unknown. RAF isoforms are commonly mutated oncogenes that serve as effector kinases in MAP kinase signaling. BRAF/CRAF heterodimers are believed to be the primary RAF signaling species, and many RAF inhibitors lead to a "paradoxical activation"of RAF kinase activity through transactivation of the CRAF protomer; this leads to resistance mechanisms and secondary tumors. It has been hypothesized that CRAF-selective inhibition might bypass paradoxical activation, but no CRAF-selective inhibitor has been reported and the consequences of pharmacologically inhibiting CRAF have remained unknown. Here, we use bio-orthogonal ligand tethering (BOLT) to selectively target inhibitors to CRAF. Our results suggest that selective CRAF inhibition promotes paradoxical activation and exemplify how BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
- Morgan, Charles W.,Dale, Ian L.,Thomas, Andrew P.,Hunt, James,Chin, Jason W.
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p. 4600 - 4606
(2021/05/04)
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- BRAF DEGRADERS
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Present invention provides compounds that cause specifically the degradation of BRAF. The present compounds are useful for the treatment of various cancers.
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Page/Page column 199-201
(2022/02/06)
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- Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4
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The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in liver regeneration and is under investigation as a target for stimulating hepatocytes to increased proliferation. Therefore, new small molecules inhibiting MKK4 may represent a promising approach for treating acute and chronic liver diseases. Fluorescently labeled compounds are useful tools for high-throughput screenings of large compound libraries. Here we utilized the azaindole-based scaffold of FDA-approved BRAF inhibitor vemurafenib 1, which displays off-target activity on MKK4, as a starting point in our fluorescent compound design. Chemical variation of the scaffold and optimization led to a selection of fluorescent 5-TAMRA derivatives which possess high binding affinities on MKK4. Compound 45 represents a suitable tool compound for Fluorescence polarization assays to identify new small-molecule inhibitors of MKK4.
- Kircher, Theresa,Pantsar, Tatu,Oder, Andreas,Peter von Kries, Jens,Juchum, Michael,Pfaffenrot, Bent,Kloevekorn, Philip,Albrecht, Wolfgang,Selig, Roland,Laufer, Stefan
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supporting information
(2020/10/22)
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- PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to MKK4 (mitogen-activated protein kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The MKK4 inhibitors selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7.
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- SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS
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The present invention relates to a process for the preparation substantially pure propane-1-sulfonicacid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenib of Formula (I). The present invention further relates to a process for the preparation substantially pure propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII)
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Paragraph 0124-0125
(2018/12/04)
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- SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS
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The present Invention relates to a process for the preparation substantially pure propane- 1 -sulfonicacid- { 3 -[5 -(4-chiorophenyI)-1 H-pyrrolo [2,3-b]pyridine-3 -carbonyl]-2,4-difluoro-phenyl} -amide or Vemurafenib of Formula (1), The present invention further relates to a process for the preparation substantially pure propane- 1 -sulfonic acid- { 3 - [5-(4-chlorophenyi)-1H-pyrrolo [2,3-b]pyridine-3 -carbonyl] -2,4-difluoro-phenyl} -amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII).
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Page/Page column 23
(2016/06/14)
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- SOLID STATE FORMS OF VEMURAFENIB HYDROCHLORIDE
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Provided herein are solid state forms of Vemurafenib hydrochloride, processes for preparing the solid state forms, as well as pharmaceutical compositions and formulations comprising said solid state forms.
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Paragraph 0055
(2014/10/15)
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- COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on each of B-Raf, B-Raf V600E and c-Raf-1 protein kinase. In certain aspects and embodiments, the described compounds are active in inhibiting proliferation of a Ras mutant cell line. Also described are methods of use thereof to treat diseases and conditions, including melanoma, glioma, glioblastoma, pilocytic astrocytoma, liver cancer, biliary tract cancer, cholangiocarcinoma, colorectal cancer, lung cancer, bladder cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical cancer, prostate cancer, gastrointestinal stromal tumors, medullary thyroid cancer, tumor angiogenesis, acute myeloid leukemia, chronic myelomonocytic leukemia, childhood acute lymphoblastic leukemia, plasma cell leukemia, and multiple myeloma.
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- PROCESS FOR THE MANUFACTURE OF PHARMACEUTICALLY ACTIVE COMPOUNDS
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According to the present invention there are provided novel processes for the manufacture of the compound of formula 1 as well as novel synthesis routes for key intermediates used in those processes.
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Page/Page column 9
(2011/02/25)
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- PYRROLO [2, 3. B] PYRIDINES WHICH INHIBIT RAF PROTEIN KINASE
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Compounds (I) and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, and forms thereof are active on each of BRaf and c-Raf -1 protein kinase, and may also be active on either or both of A-Raf and B-Raf V600E protein kinase. Also described are methods of use thereof to treat diseases and conditions, including melanoma, colorectal cancer, thyroid cancer, ovarian cancer, and biliary tract cancer.
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- PYRROLO [2, 3-B] PYRIDINE DERIVATIVES FOR THE INHIBITION OF RAF KINASES
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Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide, N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide, N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide, pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, and forms thereof are active on at least one Raf protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Raf protein kinases, including melanoma, glioma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, and biliary tract cancer.
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Page/Page column 34-35
(2010/10/03)
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- PYRROLO[2,3-B] PYRIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Compounds of formula III which are active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Page/Page column 75
(2010/11/25)
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