- Discovery of 6-[(3 S,4 S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor
-
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.
- Burke, Jason P.,Carroll, Christopher L.,Cross, Jason B.,Czako, Barbara,Di Francesco, Maria Emilia,Draetta, Giulio,Feng, Ningping,Harris, Angela L.,Heffernan, Timothy,Jiang, Yongying,Jones, Philip,Kang, Zhijun,Kohl, Nancy E.,Kovacs, Jeffrey J.,Leonard, Paul G.,Mandal, Pijus,Marszalek, Joseph. R.,McAfoos, Timothy,Meyers, Brooke A.,Mseeh, Faika,Parker, Connor A.,Sun, Yuting,Williams, Christopher C.,Wu, Qi,Yu, Simon S.
-
p. 15141 - 15169
(2021/11/01)
-
- COMBINATION THERAPY COMPRISING A2A/A2B AND PD-1/PD-L1 INHIBITORS
-
The present application provides methods of treating cancer using a combination of an inhibitor of A2A and/or A2B and an inhibitor of PD-1 and/or PD-L1.
- -
-
Page/Page column 113
(2021/07/10)
-
- CD73 INHIBITOR AND A2A/A2B ADENOSINE RECEPTOR INHIBITOR COMBINATION THERAPY
-
Disclosed are combination therapies comprising administration of a CD73 inhibitor and an adenosine A2A or A2B receptor inhibitor. The disclosed combination therapies are useful in the treatment of diseases related to the activity of adenosine receptors and/or CD73 including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases. Anti-CD73 antibodies and A2A/A2B inhibitors are also disclosed.
- -
-
Page/Page column 144
(2021/07/10)
-
- PYRAZOLOPYRIDINES AND TRIAZOLOPYRIDINES AS A2A / A2B INHIBITORS
-
This application relates to compounds of Formula (I): or pharmaceutically acceptable salts thereof, which modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors, and are useful in the treatment of diseases related to the activity of adenosine receptors including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.
- -
-
Page/Page column 42; 79
(2020/08/22)
-
- 7-Alkyl-N2-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity
-
Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N2-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N2-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram- bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10 μg/ml), and were inactive against the Gram- organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice.
- Xu, Wei-Chu,Wright, George E.,Brown, Neal C.,Long, Zheng-Yu,Zhi, Cheng-Xin,Dvoskin, Sofya,Gambino, Joseph J.,Barnes, Marjorie H.,Butler, Michelle M.
-
supporting information; experimental part
p. 4197 - 4202
(2011/08/10)
-
- Purine and isosteric antibacterial compounds
-
The invention features 2,7-disubstituted purines and their isosteres such as the corresponding 3-deazapurines and 3-deaza-8-azapurines. The compounds disclosed herein have potent anti-microbial, e.g., anti-bacterial and anti-mycoplasmal properties. The compounds described herein inhibit DNA polymerase IIIC and DNA polymerase IIIE species; the compounds thus inhibit the growth of bacteria and mycoplasmata. The compounds can be administered to prevent or to treat Gram-positive or Gram-negative bacterial or mycoplasmal infections, e.g., in eukaryotic cell cultures, animals, or humans.
- -
-
Page/Page column 10; 13
(2010/02/05)
-