Finding the USP in synthetic lethality
A flurry of activity around USP1 inhibition suggests growing interest in this novel DNA damage response mechanism.
A flurry of activity around USP1 inhibition suggests growing interest in this novel DNA damage response mechanism.
Two recent deals suggest growing interest in a new oncology mechanism involving synthetic lethality. Yesterday Exelixis paid $80m up front for rights to Insilico Medicine’s ISM3091, two months after Roche licensed rights to KSQ Therapeutics’ KSQ-4279.
Both projects inhibit USP1, a protein said to regulate DNA damage response in a manner distinct from other approaches, including PARP inhibition. Both are in phase 1 trials, and OncologyPipeline reveals a further four preclinical assets with this mechanism, one of which, Tango’s TNG348, should be in the clinic next year, having had its IND cleared last week.
The pipeline also includes Debio 0432, an asset Debiopharm licensed from Novo Nordisk in March; Novo itself had gained rights to it through last year’s $1.1bn acquisition of Forma Therapeutics, a deal primarily focused on Forma’s late-stage sickle cell project etavopivat.
During Monday’s R&D update Roche highlighted KSQ-4279, which along with the ATR inhibitor camonsertib comprised “a diversified and differentiated portfolio in DNA damage response”, it said. This year’s flurry of activity around USP1 also includes Jiangsu Simcere’s SP-002, which featured at AACR in a poster claiming preclinical activity in HRD-positive tumours, along with a claim of synergy with Lynparza.
USP1 inhibitors in development
| Project | Company EU | Status | Note |
|---|---|---|---|
| ISM3091 | Exelixis/ Insilico Medicine | Phase 1 in solid tumours | $80m up front Sep 2023; IND cleared Apr 2023 |
| KSQ-4279 | Roche/ KSQ Therapeutics | Phase 1 in solid tumours | Undisclosed up front Jul 2023 |
| TNG348 | Tango Therapeutics | IND cleared Sep 2023 | Phase 1 starting 2024 |
| Debio 0432/ FT-3171 | Debiopharm/ Novo Nordisk (ex Forma) | Preclinical | Undisclosed up front Mar 2023 |
| SP-002 | Jiangsu Simcere Pharmaceutical | Preclinical | AACR 2023 poster |
| IMP13 | Impact Therapeutics | Preclinical | – |
Source: OncologyPipeline.
Given the role of USP1 in interfering with a tumour’s DNA repair mechanisms, a concept known as synthetic lethality, and the fact it might synergise with PARP inhibitors, it's surprising not to see AstraZeneca active in this field.
Not only is the big pharma group the originator of Lynparza, it has also been involved in DNA damage repair mechanisms beyond PARP. For many years it had touted the Merck & Co-derived WEE1 inhibitor adavosertib, before discontinuing it for lack of tolerability in 2022, and its current focus seems to be on the ATR inhibitor ceralasertib.
ATR inhibition, like USP1, has been the subject of deal activity. Roche’s camonsertib, for instance, came from a $125m licensing deal with Repare Therapeutics last year, while in 2017 Merck KGaA paid Vertex $230m for rights to berzosertib.
After Roche on Monday claimed to be first in class in USP1 inhibition, Exelixis yesterday called ISM3091 a potential best-in-class approach, arising from Insilico Medicine’s generative AI technology. While KSQ-4279’s phase 1 trial already tests PARP inhibitor and chemo combos, ISM3091 is for now only being trialled as monotherapy, though Exelixis said it would accelerate enrolment.
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