Inhibitors

With years of accumulative work in the field of antibody engineering and bio-conjugation, Creative Biolabs has established a “DrugLnk” platform to introduce various new potential payloads into the development of novel antibody-drug conjugates (ADCs) for targeted therapies against cancer and other diseases.

ADCs are advanced next-generation targeted anti-cancer therapeutic agents that combines the high specificity of a monoclonal antibody with a cytotoxic drug (payload) to achieve precise drug delivery, thus reducing or ideally, eliminating the damage to healthy tissues. After binding to the surface antigen, the payload is internalized along with the antibody into the cancer cell where the payload is released from the antibody by various degradation mechanisms. The free payload subsequently diffuses to its corresponding subcellular targets and accomplishes cell killing by disrupting crucial cellular pathways.

Conventionally, microtubule toxins, DNA toxins, and transcriptional toxins have been considered the primary choices for regulating crucial cellular pathways involved in uncontrolled cancer proliferation. Various toxic agents have since been identified to selectively interact with those targets and many ADCs have been developed or are under development using these agents. Currently, a set of new subcellular targets are emerging as potential action sites accompanied by a series of corresponding small molecule inhibitors to broaden the horizon of the ADC field.

Small molecule inhibitors as new payload for ADC development. (A) Oligomycins exert anti-tumor activity as indicated by the inhibition of K-Ras (Org. Biomol. Chem., 2016); (B) Ipatasertib inhibition of the Akt pathway as indicated by the reduced expression of Akt pathway biomarkers (Clin Cancer Res, 2013); (C) a Methotrexate-carrier conjugate successfully deliver Methotrexate into the tumor cell and the subsequent drug release is mediated by carrier lysosomal degradation (J. Appl. Phys., 2014).

Oxidative phosphorylation is a crucial step in ATP production by ATP synthase complex and regulates the cellular energy level. Oligomycins, a family of macrolide spiroketal antibiotics initially used in treating infectious diseases, have been exploited in cancer treatment due to their high potency in the inhibition of oxidative phosphorylation. Another small molecule inhibitor, Ipatasertib, has also been applied in cancer treatment due to its excellent activity against protein kinase B (Atk), a serine/threonine-specific protein kinase that regulates various cellular pathways. Methotrexate, a dihydrofolate reductase (DHFR) inhibitor, has also shown great potential in cancer treatments by disturbing purine and pyrimidine synthesis, inhibiting transmethylation reactions…. Based on their unique yet versatile chemical structures, these small molecule inhibitors are under active exploration to serve as new payloads for ADC and other targeted anti-cancer therapeutics development.

With extensive experience in payload drug chemistry and bio-conjugation, the scientists at Creative Biolabs are dedicated to serve your ADC development projects with innovated small molecule inhibitor payloads. We offer comprehensive services from payload-linker complex synthesis, antibody engineering, conjugation, to basic or more sophisticated ADC biochemical and pharmacological characterizations. Please contact us for more information and a detailed quote.

References:

1. Salim, A.A.; et al. Oligomycins as inhibitors of K-Ras plasma membrane localization. Org. Biomol. Chem. 2016, 14: 711–715.
2. Lin, J.; et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013, 19(7): 1760-1772.
3. Gupta, J.; et al. Methotrexate conjugated magnetic nanoparticle for targeted drug delivery and thermal therapy. J. Appl. Phys. 2014, 115: 17B516.