gartisertib (M4344)

As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials.

Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.

In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1-phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell-cycle checkpoints, and DSB repair lowered the p53 protective barrier and extended the life of ATR inhibitor-induced DSBs...ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.

In particular, we focused on ATM/ATR involved in DNA damage response (DDR); PKM2, PDK1, LDH-A and complex I of OXPHOS involved in energy metabolism and Bcl-2/Bcl-xL involved in antiapoptotic processes.Material and MethodsH1993, H1975 and A549 oncogene-driven NSCLC cells were treated with TKIs (crizotinib, osimertinib or erlotinib) and in parallel with a combination of two of selected NOA inhibitors (DCA, benserazide, oxamate, IACS-10759, KU55933, M4344 and ABT-263). Finally, PDKs inhibition with DCA caused a significant dose-dependent decrease of glucose consumption and increase of OXPHOS subunits.ConclusionOur preliminary data suggest that targeting these proteins may destabilize tumor environment thus coupling metabolic phenotype and DDR to drug resistance. The major translational relevance of this study is to exploit these new targets for innovative and improved therapeutic strategies in comparison to TKI therapies in NSCLC patients.

P1, N=0, Withdrawn, University of Alabama at Birmingham | N=40 --> 0 | Not yet recruiting --> Withdrawn

This newly developed QSP model provides a framework that can be applied to optimize the dosing regimens of PARP and ATR inhibitor combinations and help with clinical dosing strategy.

P1, N=98, Completed, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Completed

P2, N=0, Withdrawn, EMD Serono Research & Development Institute, Inc. | N=164 --> 0 | Not yet recruiting --> Withdrawn

P1, N=98, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=300 --> 98

P2, N=164, Not yet recruiting, EMD Serono Research & Development Institute, Inc.

P1, N=300, Recruiting, EMD Serono Research & Development Institute, Inc. | N=85 --> 300 | Trial primary completion date: Nov 2020 --> Jun 2021

P1, N=85, Recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Jun 2020 --> Oct 2021 | Trial primary completion date: Jun 2020 --> Nov 2020

To identify synthetic lethal therapeutic targets to overcome chemoresistance in SLFN11 deficient cells, we performed a genome-wide RNAi screen with the human druggable genome siRNA library by using camptothecin (CPT), a TOP1 inhibitor, in SLFN11 wild-type (WT) and knock-out (KO) prostate cancer DU145 cells...Treatment with non-toxic-doses of M4344 and SRA737 reversed drug resistance of the SLFN11 KO cells to TOP1 inhibitors [CPT, and clinically used topotecan and LMP400 (indotecan)]...We also confirmed synergy with ATR/CHK1 inhibitors in combination of other clinical DNA-damaging agents (TOP2 inhibitor: etoposide, alkylating agent: cisplatin, and PARP inhibitor: talazoparib)...Co-treatment with ATR inhibitor and CPT resulted in G2/M arrest and apoptotic cell death, and formation of micronuclei and fragmented nuclei in SLFN11 KO cells, compared with SLFN11 WT cells. Collectively, our results provide a new therapeutic rationale for the clinical development of combination treatments of chemotherapeutic DNA-targeted agents with ATR/CHK1 inhibitors based on SLFN11 status.