- Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R
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Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.
- Czako, Barbara,Marszalek, Joseph. R.,Burke, Jason P.,Mandal, Pijus,Leonard, Paul G.,Cross, Jason B.,Mseeh, Faika,Jiang, Yongying,Chang, Edward Q.,Suzuki, Erika,Kovacs, Jeffrey J.,Feng, Ningping,Gera, Sonal,Harris, Angela L.,Liu, Zhen,Mullinax, Robert A.,Pang, Jihai,Parker, Connor A.,Spencer, Nakia D.,Yu, Simon S.,Wu, Qi,Tremblay, Martin R.,Mikule, Keith,Wilcoxen, Keith,Heffernan, Timothy P.,Draetta, Giulio F.,Jones, Philip
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p. 9888 - 9911
(2020/10/19)
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- Methanol as hydrogen source: Transfer hydrogenation of aromatic aldehydes with a rhodacycle
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A cyclometalated rhodium complex has been shown to perform highly selective and efficient reduction of aldehydes, deriving the hydrogen from methanol. With methanol as both the solvent and hydrogen donor under mild conditions and an open atmosphere, a wide range of aromatic aldehydes were reduced to the corresponding alcohols, without affecting other functional groups.
- Aboo, Ahmed H.,Bennett, Elliot L.,Deeprose, Mark,Robertson, Craig M.,Iggo, Jonathan A.,Xiao, Jianliang
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supporting information
p. 11805 - 11808
(2018/11/10)
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- Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols
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Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated "spin-center shift" (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report herein an enantioselective α-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.
- Nacsa, Eric D.,MacMillan, David W. C.
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supporting information
p. 3322 - 3330
(2018/03/13)
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- A strategic approach to [6,6]-bicyclic lactones: Application towards the CD fragment of DHβE
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We report an effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of t
- Jepsen, Tue Heesgaard,Glibstrup, Emil,Crestey, Fran?ois,Jensen, Anders A.,Kristensen, Jesper Langgaard
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supporting information
p. 988 - 994
(2017/06/20)
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- NOXIOUS ARTHROPOD CONTROL COMPOSITION AND HETEROCYCLIC COMPOUND
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A noxious arthropod controlling composition comprising a heterocyclic compound represented by the formula (1) [wherein, A1 and A2 represent ═C(R6)—, nitrogen and so on, R1 represents a halogen and so on, R3
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Paragraph 0754; 0755
(2013/04/13)
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- METHYL SULFANYL PYRMIDMES USEFUL AS ANTIINFLAMMATORIES, ANALGESICS, AND ANTIEPILEPTICS
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The present invention relates to pyrimidine derivatives of Formula (Ia) and (Ib) (including tautomers, isomers, prodrugs, and pharmaceutically acceptable salts thereof). Said compounds are useful in the treatment of pain (such as neuropathic pain), inflammation, and epilepsy (by acting as anticonvulsants). Methods of medical treatment making use of said compounds, as well as additional compounds of Formula (IIa) and (IIb), are also disclosed.
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Page/Page column 88
(2010/12/18)
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- AMINO-TETRAZOLES ANALOGUES AND METHODS OF USE
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A compound having Formula (I) or Formula (II) is disclosed as an P2X7 antagonist, wherein A, B, C, Y, Y, Z, m, v, R1, R2, R3, R4, and R 5, are as defined in the description. Methods and compositions for treating disease or condition modulated by P2X7 are also disclosed.
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Page/Page column 157
(2010/02/14)
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- ETUDE DES ortho-METALLATIONS REGIOSELECTIVES DE LA CHLORO-3 PYRIDINE PAR DES ORGANOLITHIENS ET DES AMIDURES DE LITHIUM; EFFET D'ORIENTATION PAR LE SOLVANT, APPLICATIONS A LA SYNTHESE
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Lithium dialkylamides metalate 3-chloropyridine with excellent regioselectivity at position 4.This reaction occurs in THF solution at -60 deg C and it leads to various 3,4-disubstituted pyridines in good yields.This regioselectivity is completely changed in ether solution by using the butyllithium-TMEDA complex.In that case position 2 is metallated and 2,3-disubstituted pyridines are obtained.
- Marsais, Francis,Breant, Patrice,Ginguene, Alain,Queguiner, Guy
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p. 139 - 147
(2007/10/02)
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