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Review
. 2025 Dec;40(1):2542357.
doi: 10.1080/14756366.2025.2542357. Epub 2025 Aug 12.

FDA-approved kinase inhibitors in PROTAC design, development and synthesis

Kacper Kossakowski  1   2 , Alina Cherniienko  1   2 , Lucjusz Zaprutko  1 , Anna Pawełczyk  1
Affiliations
Review

FDA-approved kinase inhibitors in PROTAC design, development and synthesis

Kacper Kossakowski et al. J Enzyme Inhib Med Chem. 2025 Dec.

Abstract

FDA-approved kinase inhibitors represent a rapidly growing class of targeted therapies with proven clinical success in oncology. However, their occupancy-driven mode of action is often associated with resistance, off-target effects, and incomplete inhibition. Proteolysis-Targeting Chimaeras (PROTACs) offer a compelling alternative by promoting complete degradation of oncogenic kinases, thereby enhancing selectivity and resistance reduction. In this review, we provide a comprehensive overview of the rational design, development, and synthetic approaches for PROTACs incorporating FDA-approved kinase inhibitors. We discuss key aspects influencing degrader efficiency, including kinase selectivity, linker design, E3 ligase recruitment, and synthetic strategies. Additionally, we highlight recent advances, emerging trends, and future directions, such as expanding the repertoire of degradable kinases, optimising linker chemistry, and broadening diversity of E3 ligases. A better understanding of these factors will facilitate the continued evolution of PROTAC technology into effective next-generation therapies for kinase-driven diseases.

Keywords: FDA-approved drug; Proteolysis-targeting chimaera (PROTAC); cancer; kinase inhibitor; targeted protein degradation (TPD).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
The mechanism of PROTAC-mediated targeted protein degradation (the figure was drawn by the authors using PowerPoint).
Figure 2.
Figure 2.
Flowchart of methodology (the figure was drawn by the authors using PowerPoint).
Figure 3.
Figure 3.
Structure of dasatinib and dasatinib-based PROTACs. Part I (the figure was drawn by the authors using Chemdraw software).
Figure 4.
Figure 4.
Structure of dasatinib and dasatinib-based PROTACs. Part II (the figure was drawn by the authors using Chemdraw software).
Figure 5.
Figure 5.
(a, b) Routes of synthesis of dasatinib-based PROTACs. Part I (the figure was drawn by the authors using Chemdraw software).
Figure 6.
Figure 6.
(a-c) Routes of synthesis of dasatinib-based PROTACs. Part II (the figure was drawn by the authors using Chemdraw software).
Figure 7.
Figure 7.
(a, b) Routes of synthesis of dasatinib-based PROTACs. Part III (the figure was drawn by the authors using Chemdraw software).
Figure 8.
Figure 8.
Structure of asciminib and asciminib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 9.
Figure 9.
(a, b) Routes of synthesis of asciminib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 10.
Figure 10.
Structure of ponatinib and ponatinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 11.
Figure 11.
Routes of synthesis of ponatinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 12.
Figure 12.
Structure of bosutinib and bosutinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 13.
Figure 13.
Structure of imatinib (the figure was drawn by the authors using Chemdraw software).
Figure 14.
Figure 14.
Structure of dacomitinib and dacomitinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 15.
Figure 15.
Routes of synthesis of dacomitinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 16.
Figure 16.
Structure of rociletinib and rociletinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 17.
Figure 17.
Routes of synthesis of rociletinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 18.
Figure 18.
Structure of osimertinib and osimertinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 19.
Figure 19.
Routes of synthesis of osimertinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 20.
Figure 20.
Structure of afatinib and afatinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 21.
Figure 21.
Structure of gefitinib and gefitinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 22.
Figure 22.
Routes of synthesis of gefitinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 23.
Figure 23.
Structure of dabrafenib and dabrafenib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 24.
Figure 24.
(a, b) Routes of synthesis of dabrafenib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 25.
Figure 25.
Structure of vemurafenib and vemurafenib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 26.
Figure 26.
(a, b) Routes of synthesis of vemurafenib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 27.
Figure 27.
Structure of encorafenib and encorafenib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 28.
Figure 28.
Structure of brigatinib and brigatinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 29.
Figure 29.
Routes of synthesis of brigatinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 30.
Figure 30.
Structure of alectinib and alectinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 31.
Figure 31.
Routes of synthesis of alectinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 32.
Figure 32.
Structure of crizotinib and crizotinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 33.
Figure 33.
Structure of ceritinib and ceritinib-based PROTACs. Green colour indicates palbociclib (CDK4/6 inhibitor) (the figure was drawn by the authors using Chemdraw software).
Figure 34.
Figure 34.
(a, b) Routes of synthesis of ceritinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 35.
Figure 35.
Structure of palbociclib and palbociclib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 36.
Figure 36.
Routes of synthesis of palbociclib-based PROTACs. Part I (the figure was drawn by the authors using Chemdraw software).
Figure 37.
Figure 37.
(a-c) Routes of synthesis of palbociclib-based PROTACs. Part II (the figure was drawn by the authors using Chemdraw software).
Figure 38.
Figure 38.
(a-c) Routes of synthesis of palbociclib-based PROTACs. Part III (the figure was drawn by the authors using Chemdraw software).
Figure 39.
Figure 39.
Structure of ribociclib and ribociclib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 40.
Figure 40.
Structure of abemaciclib and abemaciclib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 41.
Figure 41.
Structure of ruxolitinib and ruxolitinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 42.
Figure 42.
Routes of synthesis of ruxolitinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 43.
Figure 43.
Structure of baricitinib and baricitinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 44.
Figure 44.
Routes of synthesis of baricitinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 45.
Figure 45.
Structure of ibrutinib and ibrutinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 46.
Figure 46.
Routes of synthesis of ibrutinib-based PROTACs. Part I (the figure was drawn by the authors using Chemdraw software).
Figure 47.
Figure 47.
(a, b) Routes of synthesis of ibrutinib-based PROTACs. Part II (the figure was drawn by the authors using Chemdraw software).
Figure 48.
Figure 48.
Structure of zanubrutinib and zanubrutinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 49.
Figure 49.
Route of synthesis of zanubrutinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 50.
Figure 50.
Structure of sorafenib and sorafenib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 51.
Figure 51.
Routes of synthesis of sorafenib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 52.
Figure 52.
Structure of tepotinib and tepotinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 53.
Figure 53.
Routes of synthesis of tepotinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 54.
Figure 54.
Structure of quizartinib and quizartinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 55.
Figure 55.
(a, b) Routes of synthesis of quizartinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 56.
Figure 56.
Structure of entrectinib and entrectinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 57.
Figure 57.
Routes of synthesis of entrectinib-based PROTAC (the figure was drawn by the authors using Chemdraw software).
Figure 58.
Figure 58.
Structure of gilteritinib and gilteritinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
Figure 59.
Figure 59.
(a, b) Routes of synthesis of gilteritinib-based PROTACs (the figure was drawn by the authors using Chemdraw software).
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