Novel Bone Morphogenetic Protein Receptor Inhibitor JL5 Suppresses Tumor Cell Survival Signaling and Induces Regression of Human Lung Cancer

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2018 Apr 7

PMID 29622797

Citations 11

Authors

Jenna H Newman

David J Augeri

Rachel NeMoyer

Jyoti Malhotra

Elaine Langenfeld

Charles B Chesson

Natalie S Dobias

Michael J Lee

Saeed Tarabichi

Sachin R Jhawar

Praveen K Bommareddy

ShRae Marshall

Evita T Sadimin

John E Kerrigan

Michael Goedken

Christine Minerowicz

Salma K Jabbour

Shengguo Li

Mary O Carayannopolous

Andrew Zloza

John Langenfeld

Affiliations

Soon will be listed here.

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.

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