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Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
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Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers

Haoxuan Zhou1, Mingxing Hu1, Hui Jie2

  • 1Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China.

European Journal of Medicinal Chemistry
|September 17, 2024
PubMed

Insights

New proteolysis targeting chimera (PROTAC) molecules targeting anaplastic lymphoma kinase (ALK) fusion proteins offer a promising strategy to overcome drug resistance in ALK-driven cancers. PROTAC 4B demonstrates potent and durable ALK degradation, showing significant anti-proliferative activity in vitro and in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Anaplastic lymphoma kinase (ALK) fusion genes are key drivers in various human cancers.
  • Acquired resistance to ALK inhibitors poses a significant clinical challenge.
  • Proteolysis targeting chimera (PROTAC) technology presents a novel therapeutic approach to overcome drug resistance.

Purpose of the Study:

  • To develop and optimize novel ALK-targeting PROTACs to overcome acquired drug resistance.
  • To investigate the structure-activity relationship of ALK PROTACs.
  • To evaluate the efficacy of a lead PROTAC compound (4B) in preclinical models.

Main Methods:

  • Design and synthesis of a series of ALK PROTACs by conjugating Ceritinib with thalidomide via optimized linkers.
  • Evaluation of PROTACs' ability to induce ternary complex formation and target protein degradation.
  • In vitro assessment of anti-proliferative activity and downstream pathway inhibition in ALK-positive cancer cells.
  • In vivo efficacy studies using xenograft models and assessment of activity against drug-resistant mutations.

Main Results:

  • Subtle structural modifications in PROTACs significantly impacted their activity, highlighting the importance of PROTAC conformation.
  • Orally bioavailable PROTAC 4B demonstrated potent and sustained degradation of ALK fusion proteins in Karpas 299 cells.
  • PROTAC 4B exhibited comparable anti-proliferative activity to Ceritinib in vitro and superior activity against the G1202R mutation.
  • In vivo, PROTAC 4B significantly inhibited tumor growth in xenograft models.

Conclusions:

  • Optimized ALK PROTACs, particularly 4B, are effective in degrading ALK fusion proteins and overcoming drug resistance.
  • PROTAC 4B shows promising therapeutic potential for ALK-driven malignancies, including those with resistance mutations.
  • The study underscores the critical role of PROTAC conformation in achieving potent target degradation and therapeutic efficacy.

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