SNS-229 / Viracta Therap, Takeda - LARVOL DELTA

[VIRTUAL] PDK-1 targeting with SNS-510 in sarcoma (AACR 2021) - "In order to interrogate this in sarcoma, we elected to test SNS-510 a potent, orally bioavailable PDK1 inhibitor against a broad range of sarcoma cell lines (leiomyosarcoma, dedifferentiated liposarcoma, Ewing’s sarcoma, osteosarcoma, chondrosarcoma and synovial sarcoma) as well as dedifferentiated liposarcoma cell lines with acquired resistance to ribociclib, which are also cross resistant to palbociclib. When combined with palbociclib in both the CDK4/6 sensitive (LS141 and DDLS) and CDK4/6 resistant liposarcoma cells (RES.LS141 and RES.DDLS), we observed enhanced inhibition of proliferation with a synergistic effect, as defined by the Chou-Talalay method. These results would suggest a role for PDK-1 targeting with SNS-510 in sarcoma and consideration of combination strategies, especially with CDK4/6 inhibitors in both CDK4/6 sensitive and resistant dedifferentiated liposarcoma."

Ewing Sarcoma • Leiomyosarcoma • Liposarcoma • Oncology • Osteosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • CCND1 • CCNE1 • PDPK1 • RPS6KA3

[VIRTUAL] PDK1 inhibitor SNS-510 shows synergy with targeted cancer therapies in solid tumor and hematologic cancer models (AACR-NCI-EORTC 2020) - "Synergy was apparent at various concentration combinations of SNS-510 with CDK4/6i ribociclib and palbociclib in the ER+ breast cancer cell lines MCF7 (CDKN2b del, PI3Kca mut) and EFM19 (CDKN2A del, PI3Kca mut), with the BCL2i venetoclax in both the anaplastic large cell lymphoma SR (CDKN2a del) and the DLBCL-GCB SU-DHL-4 (TP53 mut) cell lines, and with the K-Ras G12Ci AMG-510 in the K-Ras mutated Calu-1 (lung) and Mia-PaCA-2 (pancreas) cell lines. Combination with the BTKi ibrutinib or the PI3Kdelta inhibitor umbralisib in these 2 lymphoma models did not produce strong synergy, perhaps due to partially overlapping mechanism of action... SNS-510 is a potent PDK1 inhibitor with in vitro activity as a single agent and in combination with other anticancer agents. The observed synergies support a potential role of PDK1 inhibition to reverse resistance and/or improve activity of CDK4/6i in breast cancer, BCL2i in lymphoma and K-Rasi in G12C mutated cancers. Each combination..."

Preclinical • Breast Cancer • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hormone Receptor Breast Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CDK4 • CDKN2A • CDKN2B • KRAS • PDPK1

[VIRTUAL] PDK1 inhibitor SNS-510 shows synergy with targeted cancer therapies in solid tumor and hematologic cancer models (AACR-NCI-EORTC 2020) - "Synergy was apparent at various concentration combinations of SNS-510 with CDK4/6i ribociclib and palbociclib in the ER+ breast cancer cell lines MCF7 (CDKN2b del, PI3Kca mut) and EFM19 (CDKN2A del, PI3Kca mut), with the BCL2i venetoclax in both the anaplastic large cell lymphoma SR (CDKN2a del) and the DLBCL-GCB SU-DHL-4 (TP53 mut) cell lines, and with the K-Ras G12Ci AMG-510 in the K-Ras mutated Calu-1 (lung) and Mia-PaCA-2 (pancreas) cell lines. Combination with the BTKi ibrutinib or the PI3Kdelta inhibitor umbralisib in these 2 lymphoma models did not produce strong synergy, perhaps due to partially overlapping mechanism of action... SNS-510 is a potent PDK1 inhibitor with in vitro activity as a single agent and in combination with other anticancer agents. The observed synergies support a potential role of PDK1 inhibition to reverse resistance and/or improve activity of CDK4/6i in breast cancer, BCL2i in lymphoma and K-Rasi in G12C mutated cancers. Each combination..."

Preclinical • Breast Cancer • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hormone Receptor Breast Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CDK4 • CDKN2A • CDKN2B • KRAS • PDPK1

Profiling of PDK1 inhibitor SNS-510 shows potent activity in hematologic and solid tumor cancer models and identifies CDKN2A-mutated cancers as potential targets with enhanced sensitivity (AACR-NCI-EORTC 2019) - "SNS-510 is a potent, orally bioavailable PDK1 inhibitor with broad activity in both hematologic and solid tumor cancers. SNS-510 inhibition of PDK1-signaling correlates with antitumor activity at tolerated doses and schedules in both FLT3-ITD and FLT3 wild-type AML xenograft mouse models. Profiling (anti-proliferative and molecular) in the OncoPanel cancer cell line screen identified CDKN2A mutated tumors as particularly sensitive to SNS-510, supporting a potential role by PDK1 inhibitors in combination with CDK4/6 inhibitors to reverse resistance and improve activity (Jansen Cancer Res 2017)."

Preclinical