A Small Molecule Promotes Bone Healing via P38 Activation

Background & Unmet Need

• Bone fractures are the most common impact injury that require medical attention

• About 6 million fractures occur in the US and 5 -10% of these do not heal properly

• About 10 million people in the US have osteoporosis and another 44 million people are at increased risk of developing osteoporosis due to having low bone density

• Individuals with osteoporosis are at increased risk of having a bone fracture

• Recombinant bone morphogenic proteins (BMPs) are approved to treat bone fracture healing, however, this treatment has challenges due to adverse side effects and manufacturing costs

• Unmet Need: Pharmacologically acceptable compounds to aid in bone regeneration and healing

Technology Overview

• The Technology: Small molecule inhibitors that activate osteoblast differentiation

• The Discovery: A high-throughput screen for activators of osteogenesis markers led to the identification of DIPQUO

• DIPQUO drives osteoblast differentiation by activating the β isoform of P38, leading to MAPK signaling and subsequent inhibition of GSK3-β

• PoC Data: DIPQUO treatment accelerated the differentiation of mouse myoblasts and bone-marrow derived human mesenchymal stem cells into mature osteoblasts

• DIPQUO increased the number of osteoblast cells in the caudal fins of zebrafish larvae and increased the mineralization of vertebrae in zebrafish regeneration models

• In addition to the P38 mechanism of action, DIPQUO synergized with other GSK3-β inhibitors to promote osteoblast differentiation

Technology Applications

• Small molecules to stimulate healing of bone fractures

• Therapy to treat osteoporosis and other aging-related chronic disorders associated with bone healing dysfunction

• Therapeutic for hypophosphatasia, a rare bone disease

• Research tool to study P38-β MAPK intracellular signaling in vitro and in vivo

Technology Advantages

• DIPQUO is more effective at stimulating bone deposition in comparison to BMPs

• DIPQUO is a stable small molecule that is less costly to produce at a larger scale than BMPS, which are produced as recombinant proteins

• DIPQUO accelerates bone deposition without inhibiting bone remodeling

Figure 1: DIPQUO activates p38-β MAPK signaling, which leads to differentiation of mouse myoblasts and human bone-derived stem cells into mature osteoblasts. DIPQUO also increases bone mineralization in zebrafish.