Antitumor activity of a pexidartinib bioisostere inhibiting CSF1 production and CSF1R kinase activity in human hepatocellular carcinoma

Tumor tissue is composed of a genetically heterogeneous population of cancer cells and their microenvironment (TME) which is consisted of a variety of resident and infiltrating host cells and extracellular matrix proteins [1,2]. Cancer cells are in dynamic multicellular interactions that influence tumor progression and consequently their responsiveness to therapeutics. Tumor-infiltrating immune cells, mainly lymphocytes and macrophages, attempt to inhibit tumor growth through immune surveillance function [3], however, they fail to perform anti-tumor effector functions and turn to promote tumor growth after reciprocal interactions with cancer cells [2].

Macrophages of the mononuclear phagocytic system are derived from various origins (yolk sac, bone marrow, fetal liver, and spleen) and widely distributed in various tissues [4]. Macrophages, highly plastic cells, can be changed into pro-inflammatory M1 or anti-inflammatory M2 phenotype in response to stimuli within their microenvironment. M1 phenotype is induced by interferon-γ, lipopolysaccharide, TNF-α, or granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas M2 phenotype is induced by IL-4, IL-13, TGF-β, or M-CSF. Functionally, M1 macrophages promote inflammatory response by secreting pro-inflammatory cytokines, whereas M2 macrophages produce high levels of IL-10 and TGF-β, and exhibit anti-inflammatory and wound healing properties. Tumor-associated macrophages (TAMs) are considered M2-like macrophages based on their phenotype representation, although there is evidence that TAMs have both M1 and M2 characteristics [5]. TAMs produce various growth factors, such as VEGF, EGF and TGF-β, and matrix metalloproteinases, which promote tumor growth and invasion [6]. Based on the evidence that the conversion of M2 to M1 phenotype in TME exerts tumor-suppressive effect, macrophages are highlighted as one of the targets of cancer immunotherapy [7,8].

M-CSF, also known as CSF1, is produced by a variety of cells derived from mesenchyme and epithelium [9]. During inflammatory process, recruited macrophages produce CSF1 [10], while in tumor tissues, cancer cells and other stromal cells produce CSF1 [11,12]. CSF1 action is mediated through CSF1 receptor (CSF1R, also known as M-CSF receptor or FMS), a transmembrane tyrosine kinase receptor. Normally, CSF1R is expressed primarily on monocyte-derived cells (mononuclear phagocytes), and is also expressed in some other cell types including Langerhans cells of the skin and microglia [13]. Aberrant expression of CSF1R has been found in several cancer cells derived from solid tumor of breast, prostate, ovary, kidney, and Hodgkin's lymphoma as well as from leukemias [[14], [15], [16], [17], [18], [19]]. Thus, in tumor tissues, CSF1 stimulates tumor growth with a dual action, either by stimulating cancer cell proliferation through an autocrine action [20], or by supporting tumor growth through a paracrine action by TAMs [21]. It has also been reported that the level of CSF1R-positive macrophages correlates with poor survival rate in cancer patients of various tumor types [22,23]. Based on the action mode of CSF1 and CSF1R, this axis has been targeted to suppress tumor growth and metastasis. So far, small molecule CSF1R inhibitors are in clinical trials [[24], [25], [26], [27], [28]], and pexidartinib (1, TuralioTM) with a good selectivity against CSF1R is approved to treat tenosynovial giant cell tumor, a rare disease with CSF1R over-expression [[29], [30], [31]].

In the present study, novel bioisosteres of pexidartinib (1) including compound 3, a representative one, were designed by replacement of 5-chloro-1H-pyrrolo[2,3-b]pyridine ring of pexidartinib with 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-ol ring and other similar ones (Fig. 1). Bioisoterism is one of the powerful strategies of medicinal chemistry for the rational drug design of new drugs. In anticipation of advantages such as better affinity, efficacy, druggability, and/or lower toxicity, numerous trials of exchanging a moiety of a well-known drug, a candidate, or a lead compound with a similar group of compounds has been done. A bioisostere (6) of sunitinib (5), which is currently used in the treatment of several cancers, was recently designed and prepared by us, where 5-fluoroindolin-2-one ring in the sunitinib structure was replaced by 5-hydroxy-4,6-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (6) which was prepared from a pyridin-3-ol-containing natural product, pyridoxine (4) [32]. It showed an improved safety window compared to the parent molecule, sunitinib, maintaining a similar level of anticancer activity. We here would like to report the synthesis of some bioisosteres of pexidartinib, their inhibitory activities against CSF1R, and analysis of the structure-activity relationship by molecular modeling. Moreover, compound 3, the selected compound, was further evaluated for its inhibitory activity on cancer cell proliferation, differentiation of macrophage into M1, maintenance of cancer stem cell population, and in vivo tumor growth and angiogenesis (CAM).

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