Sitravatinib (MGCD516) is an Orally Bioavailable RTK Inhibitor with PD-1 Blockade Activity
Posted On 2021-06-03
Sarcomas are rare but highly aggressive mesenchymal tumors. Mutation and overexpression of many receptor tyrosine kinases (RTKs) including c-Met, PDGFR, c-Kit and IGF1-R drive defective signaling pathways in sarcomas. Sitravatinib is a small molecule inhibitor targeting multiple receptor tyrosine kinases involved in driving sarcoma cell growth. Moreover, Sitravatinib significantly blocks phosphorylation of potential driver RTKs and induces potent anti-proliferative effects in vitro.
Sitravatinib has potent antitumor activity by targeting the tumor microenvironment, resulting in innate and adaptive immune cell changes that augment immune checkpoint blockade. Sitravatinib has the potential to combat resistance to immune checkpoint blockade and expand the number of cancer patients that are responsive to immune therapy. In addition, Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MerTK) and split tyrosine-kinase domain-containing receptors (VEGFR and PDGFR families and KIT) plus RET and MET. Furthermore, these targets contribute to the immunosuppressive tumor microenvironment. Additionally, Sitravatinib shows potent single-agent antitumor efficacy and enhanced the activity of PD-1 blockade through promoting an antitumor immune microenvironment.
In vivo, Sitravatinib has potent antitumor activity. Sitravatinib significantly inhibits tumor progression and induced tumor regression in immunocompetent mice bearing KLN205, CT1B-A5, or E0771 tumors. Furthermore, Sitravatinib treatment of tumor xenografts in vivo results in significant suppression of tumor growth. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models.
Taken together, Sitravatinib is a potent multi-kinase inhibitor in different models of sarcoma. Sitravatinib acts as a potential therapy for patients with soft-tissue sarcoma.
Parag P Patwardhan, et al. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget. 2016 Jan 26;7(4):4093-109.