The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

Abstract

Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

Bioluminescent Zebrafish Transplantation Model for Drug Discovery

“…Additionally, we demonstrated that the inhibition of proteins related to cell cycle and migration can be useful in targeting leukemic expansion in vivo . Inhibitors targeting discoidin domain receptor 1 (DDR1), BAY-826 and DDR-IN-1 are promising hits as DDR1 inhibition has potential in cancer therapy ( Elkamhawy et al, 2021 ; Berestjuk et al, 2022 ). Moreover, DDR1 therapeutic targeting in vivo was not yet characterized for the treatment of myeloid leukemia.…”

Bioluminescent zebrafish transplantation model for drug discovery

“…Additionally, we demonstrated that the inhibition of proteins related to cell cycle and migration can be useful in targeting leukemic expansion in vivo . Inhibitors targeting discoidin domain receptor 1 (DDR1), BAY-826 and DDR-IN-1 are promising hits as DDR1 inhibition has potential in cancer therapy (Berestjuk et al, 2022; Elkamhawy et al, 2021). Moreover, DDR1 therapeutic targeting in vivo was not yet characterized for the treatment of myeloid leukemia.…”

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

“…A recent study showed targeting DDR1 as a therapeutic strategy against resistance to BRAF and MEK inhibitors ( 81 ), further confirming the significance of our findings, which suggest an unprecedented role of the interactome of DDR1, BCR, and ABL1 proteins with EGFR-ERBB2-4 signaling in tumor progression. The only FDA-approved drugs currently available for DDR1 and BCR/ABL proteins are the BCR-ABL family of multi-tyrosine kinase inhibitors; however, DDR1- and BCR-ABL-specific compounds are constantly being developed ( 82 , 122 ), and a combination of DDR1-, BCR-ABL1-, and EGFR/ERBB2-4-specific drugs could co-operate, synergize, and open a new paradigm for future cancer therapeutics.…”