gw-2580 and Neoplasms

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 (

Topics: Antineoplastic Agents; Benzothiazoles; Drug Stability; Humans; Microsomes, Liver; Molecular Structure; Neoplasms; Pyrimidines; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Structure-Activity Relationship; THP-1 Cells; Tumor-Associated Macrophages

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

Topics: Animals; Antineoplastic Agents; Catalytic Domain; Cell Line, Tumor; Drug Discovery; Humans; Mice, Inbred BALB C; Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Receptor, trkA; Receptor, trkB; Receptor, trkC

The Trk family of neurotrophin receptors, which includes the three highly homologous proteins TrkA, TrkB and TrkC, is strongly associated with central and peripheral nervous system processes. Trk proteins are also of interest in oncology, since Trk activation has been observed in several cancer types. While Trk kinases are attractive oncology targets, selectivity might be more of an issue than for other kinases due to potential CNS side effects if several Trk kinases are simultaneously targeted. In order to address this issue, we present here the first structures of human TrkA and TrkB kinase domains and three complexes between TrkB and Trk inhibitors. These structures reveal different conformations of the kinase domain and suggest new regions of selectivity among the Trk family.

Topics: Amino Acid Sequence; Crystallography, X-Ray; Humans; Neoplasms; Protein Conformation; Receptor, trkA; Receptor, trkB; Sequence Alignment