Abstract 4148: An orally bioavailable small molecule antagonist of TIM-3 signaling pathway shows potent anti-tumor activity

Abstract

Activation of anti-tumor immune response by specific inhibition of PD1 pathway using monoclonal antibodies has now become of the mainstay in cancer therapy as evidenced by its widespread use in an expanding list of indications. Although these antibodies show impressive durable clinical activity, low response rates are witnessed in a large number of cancers, including colorectal cancer that remain largely refractory to PD-1 blockade. Upregulation of alternative immune checkpoints such as T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and VISTA contributes to the lack of response in patients not responding to therapies with anti-PD-1/PD-L1 antibodies. TIM-3 is a co-inhibitory receptor expressed on IFN-γ-producing T cells, FoxP3+ Treg cells and innate immune cells. Synergistic effects in restoring the anti-tumor immunity in preclinical models upon dual blockade of TIM-3 and PD-1 has provided a strong rationale for developing TIM-3 agents for use in combination with PD1 agents in the clinic. We sought to discover and develop an orally available small molecule antagonist targeting TIM3- signaling pathways. Unlike antibodies an oral agent potentially offers the convenience, flexibility to adjust dose and schedule to address any emergent adverse events and ease of combination therapy. Because TIM-3 shares sequence and structural similarity with the B7 family ligands, a focused library of compounds mimicking the interaction of checkpoint proteins of B7 family was screened towards the functional antagonism of TIM-3. Further optimization of the hit compounds resulted in lead compounds targeting TIM-3 pathway with desirable potency and selectivity. Lead compounds exhibited potent functional activity comparable to that obtained with an anti-TIM-3 antibody in rescuing the effector functions in human PBMC-based assays. Additionally, an advanced lead compound exhibited desirable drug-like properties including solubility, metabolic stability and pharmacokinetics with good oral bioavailability. In a syngeneic tumor models, once a day oral dosing of the advanced lead compound resulted in significant tumor growth inhibition as a single agent and in combination with anti-PD1 antibody that correlated well with immune PD in the tumor. The findings reported here support the development of the oral TIM-3 antagonist for use in the clinic. Citation Format: Pottayil G. Sasikumar, Sudarshan S. Naremaddepalli, Raghuveer K. Ramachandra, Nagesh Gowda, Srinivaskumar Devarapalli, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit A. Dhudashiya, Dodheri S. Samiulla, Nagaraj M. Gowda, Murali Ramachandra. An orally bioavailable small molecule antagonist of TIM-3 signaling pathway shows potent anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4148.

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

“…It was hypothesized that a substantially reduced native pharmacophore derived from protein–protein interacting interfaces of one of the B7 family protein (such as PD-1) also has the potential to interact with other proteins belonging to IgSF (such as VISTA and TIM3) with structurally similar grooves induced by pockets of sequence similarity ( 71 ). A focused library was designed and synthesized using amino acids in the hotspot region including conserved residues in the hotspot regions to identify selective or spectrum-selective inhibitors targeting one or more non-redundant checkpoint signaling pathways such as PD-L1 and VISTA ( 72 ), PD-L1 and TIM3 ( 73 , 74 ), VISTA ( 75 ), TIM-3 ( 76 ), PD-L1 and T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) ( 77 ), TIGIT ( 78 ), and cluster of differentiation 47 (CD-47) ( 79 ) pathways with desirable physicochemical properties and exposure upon oral administration. It is worth noting that small molecules with dual immune checkpoint inhibition have only been reported from the amino-acids-inspired interface mimic approach.…”