BCN077: A classic hallmark of all RAS tumor biology is the suppression of a protein known as PTEN which leads to immortalization and loss of pre programmed cell death (apoptosis) (1, 2). This is true for all forms of RAS mutations but BCN077 restore PTEN expression in the oncogenic RAS phenotype leading to rapid apoptosis in the G12V and G12D RAS mutant cancers. The restoration of PTEN expression in the oncogenic RAS phenotype allows the avoidance of resistance mechanisms of RAS inhibition where bypass signaling through N and H RAS occur (3-6).
BCN176: A first in class small molecule regulator of PD-1 expression. Historically, the approach to blocking the PD-1/PDL1 axis is to block the interaction between the two proteins with antibodies and some small molecule programs have also attempted this model but have not been successful thus far. BCN176 can potently and durably downregulate the expression of PD-1 on T-lymphocytes through the T-box transcription factors (T-bet) in the tumor microenvironment. This is a new program for BCN Biosciences and is one of a series (SAR) which are being explored a possible new model for checkpoint inhibition.
BCN512
BCN512: is one of a series of analogues (BCN500 series) which impact the development of fibrosis in the lung. This drugs are being investigated for their impact on radiation induced lung and dermal fibrosis. While they reduce lung /dermal fibrosis formation, they do not interfere with tumors (do not protect tumors from radiation or chemotherapy).
1. Vasudevan KM, Burikhanov R, Goswami A, Rangnekar VM. Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res. 2007;67(21):10343-10350. doi:10.1158/0008-5472.CAN-07-1827
2. Hill R, Calvopina JH, Kim C, et al. PTEN Loss Accelerates Kras G12D Induced Pancreatic Cancer Development. Cancer Res. 2010;70(18):7114-7124. doi:10.1158/0008-5472.CAN-10-1649
3. Ryan MB, Coker O, Sorokin A, Fella K, Barnes H, Wong E, Kanikarla P, Gao F, Zhang Y, Zhou L, Kopetz S, Corcoran RB. KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy. Cell Rep. 2022 Jun 21;39(12):110993.
5. Tanaka N, Lin JJ, Li C, et al. Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation. Cancer Discov. 2021;11(8):1913-1922.
6. Awad, M.M., Liu, S., Rybkin, I.I., Arbour, K.C., Dilly, J., Zhu, V.W., Johnson, M.L., Heist, R.S., Patil, T., Riely, G.J., et al. (2021). Acquired resistance to KRAS(G12C) inhibition in cancer. N. Engl. J. Med. 384, 2382–2393.
2. Hill R, Calvopina JH, Kim C, et al. PTEN Loss Accelerates Kras G12D Induced Pancreatic Cancer Development. Cancer Res. 2010;70(18):7114-7124. doi:10.1158/0008-5472.CAN-10-1649
3. Ryan MB, Coker O, Sorokin A, Fella K, Barnes H, Wong E, Kanikarla P, Gao F, Zhang Y, Zhou L, Kopetz S, Corcoran RB. KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy. Cell Rep. 2022 Jun 21;39(12):110993.
5. Tanaka N, Lin JJ, Li C, et al. Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation. Cancer Discov. 2021;11(8):1913-1922.
6. Awad, M.M., Liu, S., Rybkin, I.I., Arbour, K.C., Dilly, J., Zhu, V.W., Johnson, M.L., Heist, R.S., Patil, T., Riely, G.J., et al. (2021). Acquired resistance to KRAS(G12C) inhibition in cancer. N. Engl. J. Med. 384, 2382–2393.