SRC-3 treatment prolonged survival of A20-Balb/c mice.

Balb/c mice were injected with 1 x 106 A20 cells intravenously. Treatment started on day 7. A) Kaplan-Meier survival plot reflecting time to lethal tumor burden. Based on the log-rank test, there are significant differences between the treated group and the control (P < 0.05). B) Body weight of all groups were measured 5 days a week.</p

SRC-3 inhibitor treatment in normal mice show little to no toxicity after treatment for 28 days.

A) Body weight of all groups were measured 5 days a week. B) Blood serum levels of clinical markers related to kidney and liver failure. Dotted lines represent upper and lower limits based on reference values. Data outliers were removed using the identify outlier function in Graphpad Prism with the ROUT method (Q = 1%).</p

MCL cell lines were treated with SRC-3 inhibitors.

A) SI-10 or B) SI-12 at various concentrations for 48 h and cell viability was determined using the resazurin assay C) Mino D) Jeko-1 growth inhibition with SI-10 (0–1 mM) for 6,12,24, or 48h.</p

Mino parental and Mino venetoclax resistant cells were treated with various concentrations of venetoclax.

B) Jeko-1 parental and Jeko-1 ibrutinib resistant cells were treated with ibrutinib at various concentrations. C) Mino parental and resistant cells were treated with SI-10 and SI-12. D) Jeko-1 parental and resistant cells were treated with SI-10 and SI-12.</p

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Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin’s lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in vitro and demonstrated dose-dependent cytotoxicity in a panel of MCL cell lines. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes.</div

SRC-3 treatment decreased tumor growth in a Jeko-1 ibrutinib resistant mouse model.

A) Volumes of tumors treated with SI-10 (50 mg/kg), ibrutinib (100mg/kg) or vehicle B) Weight of tumors treated with SI-10 (50 mg/kg), ibrutinib (100mg/kg) or vehicle before sacrificing C) The weight of each mouse was measured 3 times a week.</p