Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

• Ponatinib is identified as a dual RIPK1 and RIPK3 inhibitor in vitro
• Ponatinib analogs, selective for RIPK1 versus Abl and RIPK2/3, are described
• Selective and potent ponatinib-Nec-1 (PN) hybrids are developed to target RIPK1
• These molecules are efficient inhibitors of TNF-α-driven pathology in vivo

SummaryRIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective “hybrid” RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies.

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