Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis

Growth hormone (GH) and insulin-like growth factor-1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10-30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA-MB-231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule

Hybrid business models for ‘Organ-on-a-Chip’ technology: The best of both worlds

Current in vitro and in vivo preclinical models often have limited predictive value for translation to the clinical setting. The emerging ‘Organ-on-a-Chip’ (OOC) technology provides a better resemblance to the human physiology through combining 3D configuration of human-derived cells with microfluidic techniques, potentially improving translation. However, due to the disruptive nature of the OOC technology, it is unclear how to best achieve a product-market fit. Data on currently employed business models was collected by 14 semi-structured interviews with representatives from OOC companies. Customer needs were collected by means of an online questionnaire among 62 (potential) end-users. Both companies and customers preferred the Hybrid business model, in which both products and services were offered. Customized services were only moderately preferred over standard services, limiting the potential for price premiums. Razor blade business models facilitate investments in laboratory equipment while locking in the purchase of disposable OOC devices. Current and future generations of in vitro technologies would benefit from combining the best of product and service business models into the Hybrid business model. Downward price pressures are expected to lead to ever-lower pricing and to facilitate more predictive, high throughput screening with a high societal impact on the longer term

Hybrid business models for ‘Organ-on-a-Chip’ technology:the best of both worlds

\u3cp\u3eCurrent in vitro and in vivo preclinical models often have limited predictive value for translation to the clinical setting. The emerging ‘Organ-on-a-Chip’ (OOC) technology provides a better resemblance to the human physiology through combining 3D configuration of human-derived cells with microfluidic techniques, potentially improving translation. However, due to the disruptive nature of the OOC technology, it is unclear how to best achieve a product-market fit. Data on currently employed business models was collected by 14 semi-structured interviews with representatives from OOC companies. Customer needs were collected by means of an online questionnaire among 62 (potential) end-users. Both companies and customers preferred the Hybrid business model, in which both products and services were offered. Customized services were only moderately preferred over standard services, limiting the potential for price premiums. Razor blade business models facilitate investments in laboratory equipment while locking in the purchase of disposable OOC devices. Current and future generations of in vitro technologies would benefit from combining the best of product and service business models into the Hybrid business model. Downward price pressures are expected to lead to ever-lower pricing and to facilitate more predictive, high throughput screening with a high societal impact on the longer term.\u3c/p\u3

Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis

Growth hormone (GH) and insulin-like growth factor-1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10-30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA-MB-231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule