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  3. Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase

Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase

  • J Med Chem. 2024 Nov 14;67(21):19736-19754. doi: 10.1021/acs.jmedchem.4c02083.
Jennifer X Qiao 1,  David Williams 1,  Patrice Gill 1,  Ling Li 1,  Derek Norris 1,  John S Tokarski 2,  Jessica Wong 3,  Huilin Qi 3,  Yamnah Hafeji 3,  Daniel P Downes 4,  Bill Degnen 4,  Ying-Kai Wang 4,  Gregory Locke 4,  Hua Fang 4,  Fei Yu 4,  Songmei Xu 4,  Joseph Naglich 4,  Jun Zhang 4,  Purushothama Nanjappa 5,  Chao Dai 5,  Lisa Chourb 6,  Jonathan Napoline 6,  Richland Tester 7,  Christine Jorge 7,  Yi-Xin Li 7,  Arvind Mathur 7,  Christopher Barbieri 4,  Matthew G Soars 6,  Avinashnarayan Venkatanarayan 3,  Emma Lees 3,  Robert M Borzilleri 1,  Ashvinikumar V Gavai 1,  Michael Wichroski 3,  T G Murali Dhar 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
  • 2 Molecular Structure & Design, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
  • 3 Oncology Discovery Biology, Mechanism of Cancer Resistance, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States.
  • 4 Leads Discovery & Optimization, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
  • 5 Discovery Pharmacology and in vivo Biology, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States.
  • 6 Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts 02141, United States.
  • 7 Department of Discovery Synthesis, Bristol Myers Squibb, Princeton, New Jersey 08540, United States.
PMID: 39437163 DOI: 10.1021/acs.jmedchem.4c02083
Abstract

We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a Cereblon binding motif (CBM) as the E3 Ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound 39. LDD 39 demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.

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