Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer

Abstract

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce Apoptosis-Inducing Factor (AIF) caspase independent cell death

“…4B). DMH2 is similar to JL5, having potent inhibition of BMP type 1 receptors with some inhibition of BMPR2 [8]. DMH2 treated cells also demonstrated an increase in DNA-DSB when used in combination with Ym155 (Fig.…”

“…Ym155 decreases BMP signaling H1299 cells were injected into the intradermal space of the anks of NSG mice and were treated with DMSO or JL5 for 4 days. We previously reported that JL5 decreases the expression of Id1 but not XIAP in tumor xenografts [8]. Survivin belongs to the family of anti-apoptotic proteins that have been reported to be regulated by BMP signaling and are known to stabilize the expression of XIAP [24].…”

“…Knockdown of BMPR2 decreases the expression of XIAP in lung cancer cell lines and increases cytosolic cytochrome c and Smac/DIABLO [22]. The BMP inhibitors JL5 and DMH2 decrease the expression of XIAP and cause more cell death than the BMP inhibitors DMH1 and LDN [7,8]. JL5 and DMH2 both demonstrate some inhibition of BMPR2 with in vitro phosphorylation kinase assays with an IC50 of approximately 8 mM [8].…”

“…The BMP inhibitors JL5 and DMH2 decrease the expression of XIAP and cause more cell death than the BMP inhibitors DMH1 and LDN [7,8]. JL5 and DMH2 both demonstrate some inhibition of BMPR2 with in vitro phosphorylation kinase assays with an IC50 of approximately 8 mM [8]. Despite JL5 having a relatively low IC50 for BMPR2 it causes its mislocalization to the cytoplasm at 2.5 mM.…”

“…In non-small cell lung carcinomas (NSCLC), the BMP-2 ligand is over-expressed 17-fold higher in comparison to normal lung tissue and benign lung tumors [4]. A number of studies have shown that BMP signaling has signi cant tumorigenic effects that involve the regulation of cell survival, migration, proliferation, stemness, and angiogenesis, and that high ligand expression correlates with a worse prognosis [3,[5][6][7][8][9][10].…”