Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

by Selleckchem | Sep 20 2023

Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.

Comments:

The discovery and characterization of NHWD-870, a potent small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins, represents a significant advancement in cancer treatment. Current BET inhibitors used in clinical stages, such as BMS-986158, OTX-015, and GSK-525762, have limitations in terms of their potency or oral bioavailability. However, NHWD-870 has demonstrated greater potency than these clinical stage inhibitors.

NHWD-870 has shown promising results in preclinical studies, exhibiting the ability to induce tumor shrinkage or significantly suppress tumor growth in nine different xenograft or syngeneic models. This suggests that NHWD-870 has potential as an effective treatment for solid tumors.

The mechanism of action of NHWD-870 involves multiple pathways. It downregulates the expression of c-MYC, a protein associated with cancer growth, and directly inhibits tumor cell proliferation. Additionally, NHWD-870 blocks the proliferation of tumor-associated macrophages (TAMs), which play a crucial role in promoting tumor growth and progression.

The inhibition of TAM proliferation by NHWD-870 is achieved through various mechanisms, one of which involves reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. CSF1 is a key factor involved in the recruitment and survival of TAMs. By inhibiting CSF1 expression, NHWD-870 effectively hampers TAM proliferation and their supportive functions within the tumor microenvironment.

The downregulation of CSF1 by NHWD-870 is mediated by its suppression of BRD4, a protein targeted by BET inhibitors, and its downstream target HIF1α. This suggests that BRD4 inhibition plays a crucial role in suppressing tumor growth by reducing CSF1 expression and subsequently inhibiting TAM proliferation.

In summary, NHWD-870 is a potent BET inhibitor that surpasses the potency of current clinical stage inhibitors. It demonstrates significant efficacy in inhibiting tumor growth through multiple mechanisms, including the downregulation of c-MYC, direct inhibition of tumor cell proliferation, and blockade of TAM proliferation by suppressing CSF1 expression. These findings provide valuable insights into the mechanism by which BRD4 inhibition suppresses tumor growth and support further development of NHWD-870 as a potential treatment for solid tumors.