ONCOLOGY & Autoimmune
Targeting the menin-MLL interaction with small molecules represents an attractive strategy to develop a new anticancer in genetically defined populations of leukemias and in certain solid cancer. A2A developed novel molecules that showed better drug-like properties, selectivity, and potency than current competitive molecules. This work is being carried out in collaboration with Biomea Fusion (TCKR: BMEA) and entered clinical trials in Q3 2021.
The transforming-acidic coiled-coil containing protein 3 (TACC3) is a nuclear protein over-expressed in many cancers leading to a worse prognosis. TACC3 has multiple functions that include mitosis, epigenetic effects, immunity, and gene transcription. A2A has developed first-in-class molecules targeting TACC3 for aggressive, hard-to-treat patient tumors as a monotherapy or in combination with standard of care. We expect to bring the first TACC3 molecule to the clinic in 2022.
FLT3, or FMS-like tyrosine kinase 3, is mutated in about 35% of acute myeloid leukemia cancers. There are classes of inhibitors that target this drug, but they cannot encompass all mutations that occur via resistance mechanisms. This higher mutant allele burden leads to a worse prognosis. The only two drugs are approved for FLT3 are Rydapt (Novartis) and Xospata (Astellas). These approved molecules are not curative and leukemias develop resistance mutations of FLT3. A2A is developing third-generation FLT3 inhibitors that molecules that have potent, broad-spectrum effects on multiple FLT3 mutations, including secondary resistance mutations.
TYK2 PSEUDOKINASE INHIBITOR
Tyrosine kinase 2 (TYK2) is a member of the Janus Tyrosine Kinase (JAK) family and is involved in several cytokine signaling pathways involved in autoimmune disorders.
Small-molecule JAK1/2 inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases., however, they are beset by toxicity problems, off-target effects and have been given the infamous “Black Box” label.
Targeting the pseudokinase domain of TYK2 has been shown to regulate particular interferons and interleukins associated with inflammation while sparing the normal cell functions. A2A is developing a best-in-class selective TYK2 pseudokinase inhibitor that aims to reduce the toxicity associated with current TYK2 inhibitors and improve upon drug-like properties ideal for chronic treatments.
KRAS, or Kirsten rat sarcoma viral oncogene homolog, is part of the 'holy-grail of protein targets and is considered an incredibly hard-to-drug target. Around 35% of various cancers have KRAS mutations and it is considered that these mutations lead to aggressive cancers leading to poor prognosis. Mutation-specific KRAS inhibitors are approved or are currently in the clinic. However, these mutation-specific inhibitors only encompass a small population of KRAS mutations found in cancer. A2A is developing a KRAS degrader approach that target all KRAS mutations and will address unmet needs for a greater patient population.
YAP-TEAD INHIBITOR / DEGRADER
The transcription factor yes-associated protein-1 (YAP) plays a central role in hippo signalling pathway, facilitating a range of pro-growth and anti-apoptotic processes. Overexpression of YAP has been characterized in patients encompassing a wide range of different cancers. Critical to YAP mediated oncogenicity is engagement with the transcription factor TEAD.
While there is extensive characterization of the essentially of the YAP-TEAD interaction in several different malignancies, there has been substantial difficulty in the development of potent inhibitors. This can be attributed to the unique topological features of the TEAD protein, particularly at the interface of the interaction with YAP. The SCULPT platform enables the chemical tractablilty of this unique architecture through several dozen iterations of molecular design.