Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening

Abstract

The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by the human genome share highly conserved catalytic domains. Until now, no selective inhibitors unique for a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein receptor type 2 (BMPR2), have been reported. This dearth of receptor-specific kinase inhibitors hinders therapeutic options for skeletal defects and cancer as a result of an overactivated BMP signaling pathway. By screening 4.17 billion "unbiased" and "kinase-biased" DNA-encoded chemical library molecules, we identified hits CDD-1115 and CDD-1431, respectively, that were low-nanomolar selective kinase inhibitors of BMPR2. Structure−activity relationship studies addressed metabolic lability and high-molecular-weight issues, resulting in potent and BMPR2-selective inhibitor analogs CDD-1281 (IC 50 = 1.2 nM) and CDD-1653 (IC 50 = 2.8 nM), respectively. Our work demonstrates that DNA-encoded chemistry technology (DEC-Tec) is reliable for identifying novel first-in-class, highly potent, and selective kinase inhibitors.

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

“… Chemical structures of BMPR-II inhibitors . The recently disclosed first-in-class BMPR2 (i.e., one of the three type II receptors) inhibitors CDD-1653 and Compound 8a feature a 2,4-diamino­pyrimidine core scaffold but are classified as distinct chemotypes based on their putatively different hinge-binding motifs. , …”

Strategies for Competitive Activity‐Based Protein Profiling in Small Molecule Inhibitor Discovery and Characterization

“…After capture of the magnetic beads, test compound selectivity is assessed by qPCR to quantify kinases that remain bound to the solid phase ABP. This platform has been widely used for the development of kinase inhibitors [55b,58] …”

Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2

“…These compounds affect BMPR2 in the low nanomolar range, but they also showed potent inhibition of ALK1, ALK2, ALK3, TGFBR2, and VEGFR2 . More recently, Modukuri et al have identified selective benzimidazole-based potent inhibitors (CDD-1115, CDD-1653) of BMPR2 by using a DNA-encoded chemistry technology (Figure A) …”

“…29 More recently, Modukuri et al have identified selective benzimidazole-based potent inhibitors (CDD-1115, CDD-1653) of BMPR2 by using a DNA-encoded chemistry technology (Figure 1A). 30 Compound 1 is a promiscuous kinase inhibitor developed by Statsuk et al A kinome-wide scan against 468 recombinant human protein kinases emphasized the promiscuous behavior of 1, which potently inhibits 262 kinases (Figure 1B, C). In this report, type-I and type-II BMP-receptor kinases were potently targeted.…”

“…A. Chemical structures of JNJ-28312141, nintedanib, dorsomorphin, sunitinib, CDD-1115, and CDD-1653, with the corresponding K D and IC 50 values reported for BMPR2. ,, B. Selectivity profile of 1 at 1 μM. The chemical structure of 1 is shown beside the dendrogram .…”