Delving into the Latest Updates on UPR-1444 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

EGFR C797S

Mechanism

EGFR C797S inhibitors(Epidermal Growth Factor Receptor C797S inhibitors)

Therapeutic Areas

NeoplasmsRespiratory Diseases

Active Indication

Non-Small Cell Lung Cancer

Inactive Indication-

Originator Organization

University of Parma

Active Organization

University of Parma

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

The emergence of the C797S mutation in EGFR is a frequent mechanism of resistance to osimertinib in the treatment of non-small cell lung cancer (NSCLC). In the present work, we report the design, synthesis and biochemical characterization of UPR1444 (compound 11), a new sulfonyl fluoride derivative which potently and irreversibly inhibits EGFR^{L858R/T790M/C797S} through the formation of a sulfonamide bond with the catalytic residue Lys745. Enzymatic assays show that compound 11 displayed an inhibitory activity on EGFR^WT comparable to that of osimertinib, and it resulted more selective than the sulfonyl fluoride probe XO44, recently reported to inhibit a significant part of the kinome. Neither compound 11 nor XO44 inhibited EGFR^{del19/T790M/C797S} triple mutant. When tested in Ba/F3 cells expressing EGFR^{L858R/T790M/C797S}, compound 11 resulted significantly more potent than osimertinib at inhibiting both EGFR autophosphorylation and proliferation, even if the inhibition of EGFR autophosphorylation by compound 11 in Ba/F3 cells was not long lasting.

100 Deals associated with UPR-1444

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