8:30 am Coffee & Networking
8:50 am Chair’s Opening Remarks
TACKLING DDR INHIBITOR TOXICITY THROUGH DOSE SCHEDULING & OPTIMIZING TREATMENT PLANS
9:00 am Prioritizing Patient Selection for Combination Studies to Optimize Treatments
Synopsis
• Calibrate the value of personalized treatments for heterogeneous patient populations
• Refine patient selection beyond only genomic screening to consider disease progression and metastases
• Reflect on accessibility of clinical samples for screening and imaging
9:30 am Roundtable & Feedback Panel Discussion: What Defines Clinical Success for Current & Next-Generation DDR Inhibitors?
Synopsis
• Can DDR inhibitors overcome the challenges other precision oncology therapies have faced?
• Is maintenance and preventing cancer progression enough?
• When should we pursue combination therapies for patients?
10:30 am Morning Break
DISCOVERY TRACK
Overlapping Toxicity & Overlapping Efficacy of Novel DDR Combination Therapies
11:30 am NP1867: A Chemical Probe for Exploring the Role of DNA Mismatch Repair in Human Disease
Synopsis
• MMR-deficient (MMR-d) tumors are eligible for immune checkpoint therapy, irrespective of tumors type, providing substantial clinical benefit; however, not all MMR-d patients respond to CPI therapy and correlation of tumors mutational burden with clinical outcome is controversial
• Small molecule NP1867 potently and selectively binds to the MutLa heterodimer component PMS2 enabling acute and chronic, dose- and time-dependent, MMR inhibition without removal of the target protein
• NP1867, and appropriate controls, reveal that PMS2 binding inhibits DNA Mismatch Repair in cell-based mechanistic and functional assays, elicits COSMIC mutational signatures consistent with MMR-d patient populations, and renders treated tumour cells immunogenic
12:00 pm ATR & ATM Mode of Action & Therapeutic Potential
Synopsis
• Establishing potential therapeutic and toxicity synergies of DDR combination therapies
• A priori determination of potential toxicity though biological rational of combination choice to streamline discovery
• Delivering optimal potency of novel molecules through optimized chemistry for combination
PRECLINICAL & CLINICAL TRACK
Innovating DDR Molecules to Address Unmet Need
11:30 am SGR-2921, A Clinical Stage CDC7 Inhibitor, Enhances DNA Damage, Replication Stress and Apoptosis in AML Tumor Models
Synopsis
• Schrodinger’s physics-based technology facilitated the discovery of highly potent CDC7 inhibitors, including SGR-2921 which demonstrates strong anti-leukemic activity in various preclinical models of AML mediated through mechanisms that exploit DNA damage and ultimately cell death, which are secondary to enhanced replication stress
• Compelling preclinical activity across various molecular genetic contexts of AML and optimization of SGR-2921 dose and schedule support exploring CDC7 inhibition as a new approach for AML and SGR-2921 as a potential combination partner to current standard-of-care agents
• SGR-2921 is currently being explored in a Phase 1 trial of relapsed/refractory AML and MDS including in patients with p53m disease, potentially providing a unique theapeutic option for this underserved population
12:00 pm IDE161, a Potential First-in-Class Clinical Candidate PARG Inhibitor, Selectively Targets DNA Repair Deficient Solid Tumors
Synopsis
• PARG plays a pivotal role in the maintenance of cancer genome stability through resolution of DNA damage and replication stress
• IDE161 is a potent and selective small molecule PARGi with anti-tumor activity in biomarker defined settings and is currently in clinical development as an anti‑cancer therapeutic for patients with advanced or metastatic cancer
• IDE161’s anti-tumor activity is distinct from PARP inhibition
12:30 pm Lunch
MAXIMIZE DDR THERAPEUTIC SUCCESS THROUGH OPTIMIZED CHEMISTRY AND BBB PENETRATION
1:30 pm Unlocking the potential of CHK1: Discovery of BBI-355, the First ecDNADirected Therapy (ecDTx) for the Treatment of Oncogene Amplified Cancers
Synopsis
• Addressing unmet need of oncogene driven cancers
• Development of CHK1 inhibitor to disrupt cell cycle and cell survival in tumors
2:00 pm Drug Distribution Across the Blood-Brain Tumor-Barrier & Maximizing the Efficacy of DDR Inhibitors in GBM
Synopsis
• Define the extent of BBTB disruption in human GBM
• Evaluate the impact on heterogeneous drug delivery across the BBTB on efficacy
• Consider the effects of drug distribution into normal brain on radiation toxicity
2:30 pm Afternoon Break
VENTURING BEYOND ONCOLOGY FOR DDR INHIBITORS
3:30 pm What is Next for DDR Inhibitors Outside Oncology?
Synopsis
• Rethink what disorders could be treated with DDR inhibitors
• Incorporating lessons from oncology and ponder DDR inhibitors for fibrosis