TNG961 is a selective oral HBS1L molecular glue degrader for the treatment of FOCAD-deleted cancers

  • Cancer Discov. 2026 Apr 19. doi: 10.1158/2159-8290.CD-26-0040.
Hilary E Nicholson  1 ,  Douglas A Whittington  2 ,  Frank J Bruzzese  2 ,  Katherine Lazarides  3 ,  Lauren Catherine M Martires  4 ,  Matthew R Tonini  5 ,  Helena N Jenkins  2 ,  Minjie Zhang  4 ,  Preksha Shahagadkar  2 ,  Charlotte B Pratt  2 ,  Kimberly J Briggs  6 ,  Patrick McCarren  2 ,  Alice Tsai  5 ,  Madhavi Bandi  4 ,  Chengyin Min  2 ,  Alan Huang  2 ,  Hongxiang Zhang  4 ,  Samuel R Meier  2 ,  Binzhang Shen  5 ,  Yi Yu  4 ,  Colin Liang  2 ,  Yong Liu  2 ,  Teng Teng  1 ,  John Zhang  2 ,  Adam Crystal  2 ,  William D Mallender  2 ,  Xinyuan Edward Wu  2 ,  John P Maxwell  2 ,  Jannik N Andersen  3
Affiliations
  • 1. Tango Therapeutics (United States) Boston United States.
  • 2. Tango Therapeutics (United States) Boston, MA United States.
  • 3. Tango Therapeutics (United States) Boston, Massachusetts United States.
  • 4. Tango Therapeutics (United States) Cambridge, MA United States.
  • 5. Tango Therapeutics Boston, MA United States.
  • 6. Tango Therapeutics Boston United States.
PMID: 42001523 DOI: 10.1158/2159-8290.CD-26-0040
Abstract

When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor gene CDKN2A, creating synthetic lethal dependency on PRMT5. Telomeric to MTAP lies FOCAD, whose loss induces dependency on the HBS1L/PELO ribosome-rescue complex for translational maintenance. FOCAD is deleted in ~1/3 of MTAP-deleted cancers. We screened an IMiD-focused diversity library and identified a weak hit that bound Cereblon, promoted HBS1L-CRBN-compound complex formation, and induced E3-ligase-dependent HBS1L ubiquitination and degradation. Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.

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