TNG-348: A Comprehensive Review of a USP1 Inhibitor for HRD+ Cancers

1. Introduction to TNG-348

TNG-348 emerged as an orally bioavailable, small molecule inhibitor designed to target the ubiquitin-specific protease 1 (USP1).[1] Its development was rooted in the principle of synthetic lethality, aiming to exploit specific vulnerabilities in cancer cells with deficient DNA repair mechanisms.[2]

1.1. Chemical Identity and Basic Properties

TNG-348 is chemically identified by the CAS Number 2839740-79-1.[2] Its molecular formula is C27​H23​F6​N9​O, corresponding to a molecular weight of 603.5 g/mol.[2] For computational drug-like property assessment, its CLogP (a measure of lipophilicity) is 3, and its Topological Polar Surface Area (TPSA) is 104 Ų.[2] These parameters are crucial in early drug development for predicting pharmacokinetic properties such as absorption and membrane permeability. The SMILES (Simplified Molecular Input Line Entry System) string for TNG-348 is CN1C=C(N=C1C2=CC=C(C=C2)CN3C4=NC(=NC=C4N(C3=N)CC(F)(F)F)C5=C(N=CN=C5OC)C6CC6)C(F)(F)F.[2]

1.2. Developer and Origin

TNG-348 was developed by Tango Therapeutics, a clinical-stage biotechnology company specializing in precision oncology and synthetic lethality.[2] The foundational preclinical USP1 inhibitor program that led to the discovery and development of TNG-348 was in-licensed by Tango Therapeutics from Medivir AB in 2020.[4] This collaboration highlights a common strategy in the pharmaceutical industry where specialized biotechnology companies advance promising preclinical assets originating from other research entities. Tango Therapeutics' focus on synthetic lethality suggests that the precursor program from Medivir demonstrated significant potential in selectively targeting cancer cells with specific DNA repair deficiencies, aligning with Tango's core research and development strategy.

1.3. Therapeutic Class