Diacylglycerol kinase A (DGKA) Inhibitor: Treating solid tumors in combination with checkpoint inhibitor
Assays Completed
Owned and Available for Licensing
In vivo efficacy studies – Single agent and combo study with anti-CTLA4, anti-PD-1
In vivo efficacy studies – Single agent and combo study with anti-PD-1
In vivo PK-PD
In vivo PK studies
In vitro ADMET studies
In vitro cell-based
Toxicology studies
Target Rationale
Diacylglycerol kinases (DGKs), belong to a family of isozymes that phosphorylate the membrane lipid diacylglycerol (DAG) to phosphatidic acid (PA), both of which are important players in T cell signal transduction cascades. DAG and PA act as vital second messengers that regulate multiple cellular signal transduction pathways including PKC and MAPK.

DGKα (DGKA) is one of the ten human DGK isoforms that has been reported to play a role in mediating numerous aspects of cancer progression including survival, migration, and invasion of cancer cells. Emerging data indicates that DGKA mediates T-cell dysfunction during anti-PD-1 therapy, playing a role in the development of resistance to PD-1 blockade. This in turn suggests that DGKA inhibition offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer. Although the serotonin (5-HT) antagonists ritanserin, R59022 and R59949 have been previously repurposed as DGKA inhibitors, their potency and selectivity profiles are largely suboptimal. Hence, there is a significant unmet clinical need to develop potent and selective DGKA inhibitors.
DGKA controls the magnitude of the TCR response and T cell anergy.
Front. Cell Dev. Biol., 03 March 2017

Insilico Medicine DGKA Inhibitor Summary – IND-Enabling
Novel structure generated by AI
  • Distinctly novel structure generated by Insilico Medicine's AI small molecule generation platform Chemistry 42
  • DGKA was proposed by Insilico Medicine's AI target discovery engine platform PandaOmics
  • A potential best in class candidate
Robust in vitro and in vivo efficacy
  • Excellent in vitro enzymatic and cellular activity
  • Robust in vivo antitumor activity in various models and potent synergy in combination with PD-1 or CTLA-4
  • Low predicted dose in humans
Promising drug-ability as an oral single/combo agent
  • Excellent in vitro ADME profile
  • Promising PK profiles across different preclinical animal species
  • High selectivity in KinomeScan and Cerep panels
Favorable safety margin
  • Good safety margin in rat and mouse studies without severe side effects
  • Excellent in vitro safety profiles

PD-1/PD-L1 axis blockade has been highly efficient in some cancers however, a sizable number of patients regress over time while other cancer types remain refractive to PD-1/PD-L1 axis blockade from the get-go. Therefore, a sizeable unmet need exists for therapeutic strategies that can counteract anti-PD-1/PD-L1 resistance mechanisms. Mechanisms of anti-PD-1/-L1 resistance are multi-faceted and encompass the breadth of the cancer immunity cycle, from initial tumor cell death and subsequent antigen presentation, right through to T cell activation and infiltration to the tumor bed where T cells can kill their tumor targets and restart the cycle. Our PandaOmics Target ID Engine was employed to distinguish the key drivers of PD-1/PD-L1 therapy resistance, thereby providing a rationale to augment the effect of the checkpoint inhibition. This was accomplished by comparing the expression profiles of responders versus non-responders to derive the causality of immune escape.

DGKA mediated T-cell dysfunction during anti–PD-1 therapy is characterized by the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of DGKA postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade.

DGKA inhibitors offer a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer:
Combination with checkpoint inhibitors
  • Checkpoint inhibitor non-responder or acquired resistance patients
  • Checkpoint inhibitor low-responder patients

Project Status – IND-Enabling
We used our proprietary PandaOmics platform to explore targets that can overcome resistance to anti-PD-1/-L1 therapy. DGKA inhibition was identified as an approach that may overcome anti-PD-1/-L1 resistance and expand the responder patient population for cancer immunotherapy. We next designed and evaluated a series of compounds using biochemical and cellular assays and identified a novel DGKA inhibitor with excellent potency and high selectivity for DGKA versus 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2B. Further, this novel inhibitor showed high selectivity against 468 other kinases. In cellular T-cell activation assays, our inhibitor induced IL-2 production in a dose-dependent manner and enhanced T-cell activity at low concentrations. Tumor growth inhibition was observed in mouse models including potent synergy with anti-PD-1 therapy.