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  • thrombopoietin receptor agonist br Data deposition The struc

    2019-07-15


    Data deposition: The structure factor amplitudes and coordinates of mIL34 and the mIL-34:mCSF-1R complex have been deposited in the Protein Data Bank, www.pdb.org, with accession codes 4EXN and 4EXP. Note added in proof The authors would like to inform the readers of two recent articles that are relevant for this study but were not discussed and thus omitted from this paper, see refs. [32], [33]. Ref. [33] appeared in the course of our submission.
    CSF-1R is a member of the class III receptor tyrosine kinases, along with c-Kit, Flt3, and PDGFR α and β. Colony stimulatory factor 1 (CSF-1), also known as macrophage/monocyte colony stimulatory factor (M-CSF), binds to CSF-1R, resulting in dimerization, autophosphorylation, and activation of signal transduction. CSF-1/CSF-1R signaling is essential for normal monocyte development, trophoblastic implantation, and mammary gland development during pregnancy and lactation., In cancer, pro-tumorigenic macrophages have been identified and linked to poor prognosis in breast, ovarian, and prostate cancers., Elevated levels of CSF-1 and CSF-1R have been reported in several tumor types, including breast, ovarian, and endometrial cancers, and have also been linked to invasion and metastasis. Inhibition of CSF-1R activity could therefore have multiple effects on the tumor through reduction in the levels of tumor-associated macrophages (TAMs) and have direct effects on the tumor itself. Compounds with activity against the other class III RTKs and KDR, such as Sutent and ABT-869, have been reported as inhibitors of CSF-1R. As yet, no selective small molecule has entered clinical trials, although PD0360324, a monoclonal antibody from Pfizer, recently entered phase I for the treatment of rheumatoid arthritis. Other structural types have been reported as CSF-1R inhibitors, with some targeting inflammation rather than cancer indications., , , , , , , Subset screening of our thrombopoietin receptor agonist collection identified diaminophenyl bisamides as CSF-1R inhibitors, with () being the most potent of these (CSF-1R IC 89nM). Within AstraZeneca, compounds from this scaffold had previously been explored as inhibitors of p38 MAP kinase. Other groups have found related compounds to be inhibitors of Lck and c-Kit. Activity was retained when the quinoline was replaced with other bicyclic ring systems such as quinoxaline or benzothiazole. A variety of substituents on the left-hand side aryl ring, especially at the 3-position, were also tolerated (data not included). Despite good activity in both enzyme and cell assays, compounds of this type suffered from low aqueous solubility and high plasma protein binding. The relatively high molecular weights limited options to improve the physical properties. The replacement of the quinoline with a 3-pyridyl group reduced both the MW and lipophilicity, and of the four possible configurations of the amide bonds (), three compounds (–) demonstrated good enzyme activity, with having good activity in our cell proliferation assay (). In our hands, Sutent had a CSF-1R enzyme IC of 12nM, and cell activity of 0.09μM, consistent with literature data., Replacing methyl with chloro on the central ring of pyridyl bisamide improved activity (, ), with small lipophilic groups at the 3-; 3,4-; and 3,5-positions giving excellent cell potency (, –). Replacing the pyridyl ring with phenyl () destroyed activity, suggesting that the pyridine N makes a key H-bond interaction with the protein. Examples from this set of compounds were found to have acceptable oral PK properties in rats, with moderate or low in vivo clearance and good bioavailability (). Compounds from this series were also active against another AstraZeneca kinase target, B-Raf. Replacing the 3-pyridyl with other six-membered heterocycles gave less potent compounds for both CSF-1R and B-Raf. However, modeling studies within our B-Raf program suggested a thiazole ring as an alternative to the pyridine. Compounds of this type (, –) also had good in vitro potency for CSF-1R; about twofold less active in the cell assay than the corresponding pyridyl examples (, , , and ). 2-Methylthiazole derivatives were more potent than the corresponding pyridyl compounds; isopropyl and cyclopropyl groups were also tolerated at the thiazole 2-position. The SAR established for the pyridyl series transferred closely to the thiazolyl bisamides.