SY-5609

The antifungal activity of SY-1365 was also markedly enhanced in combination with membrane-targeting antifungals. Together, our findings highlight CDK7 inhibitors as valuable tools to study CDK7 function in Cn and as potentially promising antifungals in combination with licensed antifungals.

P1, N=542, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2029 --> Nov 2028

Therefore, it can be used in structure-assisted design of CDK7 inhibitors, as demonstrated by the crystal structure of the complex with inhibitor SY5609. CDK2m7 thus represents a simple and affordable platform for CDK7 rational drug design.

P1, N=542, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells.  A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML.

P1, N=422, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Apr 2026 --> Nov 2029 | Trial primary completion date: Sep 2025 --> Aug 2027 | Recruiting --> Active, not recruiting

P1, N=422, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P1, N=422, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=422, Recruiting, Hoffmann-La Roche | Trial completion date: Aug 2026 --> Apr 2026

Treatment with JAK inhibitor (JAKi), e.g., ruxolitinib, venetoclax or hypomethylating agents alone or in combination are ineffective in improving the poor survival in MPN-sAML...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and clinical grade SY-5609, dose-dependently (20 to 250 nM) increased % G1 while reducing the % of cell-cycle S phase SET2 and HEL cells...SY-5609 treatment also exerted synergistic lethality with the BETi pelabresib or BD2-selective BETi ABBV-744 or the CBP/p300 inhibitor GNE-049 in MPN-sAML cells...Additionally, compared to each drug or vehicle control, co-treatment with SY-5609 and OTX015 (30 mg/kg/day by oral gavage) reduced more MPN-sAML burden and significantly improved survival in a HEL-Luc/GFP xenograft model without inducing toxicity. These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to further evaluate in vivo efficacy of CDK7i-based combinations against advanced MPN with excess blasts or MPN-sAML.

P1, N=105, Completed, Syros Pharmaceuticals | Active, not recruiting --> Completed | N=160 --> 105 | Trial completion date: Jul 2024 --> Mar 2023 | Trial primary completion date: Jul 2023 --> Jan 2023

P1, N=340, Recruiting, Hoffmann-La Roche | Trial completion date: Jan 2026 --> Aug 2026