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KSQ® Therapeutics Presents First Preclinical Data for KSQ-4279, a Novel USP1 Inhibitor, for the Treatment of BRCA-Deficient Cancers

2020 ENA Plenary Slide Deck: “USP1 inhibitors show robust combination activity and a distinct resistance profile from PARP inhibitors”

2020 ENA Poster: “Development of KSQ-4279 as a first-in-class USP1 inhibitor for the treatment of BRCA-deficient cancers”

  • Data demonstrate robust single agent, combination activity and distinct resistance profile from PARP inhibitors

CAMBRIDGE, Mass., October 24, 2020 – KSQ Therapeutics, a biotechnology company using its proprietary CRISPRomics® discovery platform to systematically screen the whole genome to identify optimal gene targets for oncology and autoimmune disease, today announced the first preclinical data for its lead program, KSQ-4279, a ubiquitin specific peptidase 1 (USP1) inhibitor being evaluated in targeted oncology. KSQ-4279 is a potential first-in-class inhibitor of USP1, a gene target that was identified and validated using KSQ’s CRISPRomics platform. The data presentations include a plenary session entitled, “USP1 inhibitors show robust combination activity and a distinct resistance profile from PARP inhibitors” and a poster session entitled, “Development of KSQ-4279 as a first-in-class USP1 inhibitor for the treatment of BRCA-deficient cancers”. The data to be presented at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (ENA 2020) illustrate the potential of KSQ-4279 for the treatment of ovarian and triple negative breast (TNBC) cancers. KSQ-4279 showed dose-dependent tumor growth inhibition as a single agent as well as in combination with a PARP inhibitor in BRCA-deficient preclinical models.

“These data provide convincing evidence that USP1 is an attractive druggable target that inhibits different yet complementary DNA repair pathways than PARPs and that our lead molecule is both potent and selective when tested across multiple tumor models,” said Frank Stegmeier, Ph.D., Chief Scientific Officer of KSQ Therapeutics. “The data show that KSQ-4279 has significant potential when combined with standard of care regimens such as PARP inhibitors. Together these data convey a compelling story about the potential of this program in a variety of cancers and treatment scenarios, giving us confidence to advance KSQ-4279 into clinical evaluation as a novel agent in a new class of targeted oncology treatment. This also further validates the ability of our platform to generate novel, high value drug targets agnostic of therapeutic area or modality.”

PARP inhibitors provide significant clinical benefit for many cancer patients with BRCA1/2 mutations and other homologous repair deficiencies (HRD), but not all patients respond, and of those that do, many go on to develop resistance. KSQ utilized its proprietary CRISPRomics platform to identify the deubiquitinating enzyme USP1 as an attractive cancer target with established roles in DNA damage repair processes that are distinct from PARP inhibitors and other approaches currently being tested in the clinic. Potent, selective inhibitors of USP1 were developed and tested across a broad range of tumor lineages with varied genetic backgrounds. Sensitivity to the lead drug candidate, KSQ-4279, was enriched in cancers with genetic alterations in BRCA1/2 or other HRD lesions.

In vitro cancer cell screens using CRISPRomics technology were used to investigate the mechanism of action and resistance profiles of USP1 and PARP inhibitors. The selectivity and potency of KSQ-4279 was evaluated in vitro and efficacy and tolerability were assessed in vivo using daily oral dosing of KSQ-4279, olaparib, or both agents together at pharmacologically-relevant doses.

Key conclusions from both presentations include:

  • KSQ-4279 induces cell cycle arrest and DNA damage leading to apoptosis and cell death in BRCA1 mutant cells
  • Functional genomic resistance screens indicate that the top scoring resistance genes differ between USP1 inhibitors and PARP inhibitors and were functionally related to their distinct mechanisms of action
  • KSQ-4279 is active as a monotherapy in an ovarian PDX model, showing dose-dependent tumor growth inhibition at 100 mg/kg and 300 mg/kg of 102% and 105% versus control, respectively
  • The combination of KSQ-4279 with a PARP inhibitor led to more pronounced anti-tumor activity than either agent alone across multiple ovarian and TNBC PDX models, leading to durable tumor regressions in settings where PARP inhibitors only achieved partial tumor control
  • Preliminary safety data indicate that KSQ-4279 is well-tolerated as a single agent and in combination with olaparib with no evidence of dose-limiting hematologic-related toxicities

The poster titled, “Development of KSQ-4279 as a first-in-class USP1 inhibitor for the treatment of BRCA-deficient cancers” and the plenary presentation titled, “USP1 inhibitors show robust combination activity and a distinct resistance profile from PARP inhibitors” are available on the KSQ website.

About KSQ-4279 and USP1 Inhibition

USP1 is a member of the ubiquitin-specific processing (UBP) family of proteases. USP1 regulates DNA damage response (DDR) pathways by deubiquitinating specific proteins in the Fanconi Anemia (FA) and Translesion Synthesis (TLS) pathways. These DNA repair mechanisms are not currently targeted by any compounds in clinical testing. PARP inhibitors, which target a distinct DNA repair mechanism, have shown significant clinical utility and opened up a new field of targeted oncology drugs that exploit synthetic lethality. The discoveries from our CRISPRomics platform revealed that USP1 inhibition also leads to sensitivity of cell lines with BRCA/HRD alterations in addition to a specific subset of cell lines from other solid tumor indications. Our lead USP1 inhibitor, KSQ-4279, demonstrated potent and selective inhibition of USP1 as a single agent and showed a combination advantage with PARP inhibitors across multiple in vivo models.

About KSQ Therapeutics

KSQ Therapeutics is advancing a pipeline of tumor- and immune-focused drug candidates for the treatment of cancer across multiple drug modalities including targeted therapies, adoptive cell therapies and immuno-therapies. KSQ’s proprietary CRISPRomics® discovery engine enables genome-scale, in vivo validated, unbiased drug discovery across broad therapeutic areas. KSQ was founded by thought leaders in the field of functional genomics and pioneers of CRISPR screening technologies. For more information, please visit the company’s website at and follow @ksq_tx on Twitter.

Media Contact:

Cory Tromblee
Tel: 617-571-7220

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