Advancing best-in-
class and first-in-class candidates
HER2, including oncogenic mutations
IAM1363 is a highly potent and irreversible tyrosine kinase inhibitor (TKI) that selectively targets HER2 and HER2 mutants, while sparing EGFR. Amplification and mutations of HER2 drive a wide range of human cancers. HER2 TKIs have had limited success due to a compensatory mechanism that increases the required therapeutic index beyond that of available pan-ERBB and HER2 inhibitors.
IAM1363 exhibits over 1000-fold selectivity against EGFR, favorable PK and safety profiles, preferential tumor enrichment, and effective CNS penetrance. Together these make IAM1363 a breakthrough molecule for realizing the full therapeutic potential of inhibiting HER2 signaling, while avoiding EGFR-driven toxicity. In vivo, IAM1363 has demonstrated favorable efficacy and tolerability across a range of HER2 tumor models, including intracranial models, outperforming benchmark TKIs and antibody-drug conjugates (ADCs).
In March 2024, patient dosing commenced in a multi-center Phase 1 trial.
CDK2/4
IAM-C1 is a first-in-class small molecule inhibitor designed to specifically target CDK2 and CDK4, two cell-cycle kinases that are frequently dysregulated in various cancers. Through its selective inhibition of CDK2/4 while preserving other closely related CDKs including CDK1, CDK6, and CDK9, IAM-C1 has the potential to provide expanded therapeutic benefits compared to clinically approved CDK4/6 inhibitors.
IAM-C1 represents a promising new approach to address cell-cycle dysregulation in cancer, building upon the learnings from two decades of research and clinical experience. CDK4/6 inhibitors are the standard of care for patients with HR+/HER2- metastatic breast cancer (mBC) in both first- and subsequent-line settings. Despite the success of these agents, many patients demonstrate either intrinsic or acquired resistance to the approved CDK4/6 inhibitors. HR+/HER2- mBC remains a significant cause of morbidity and mortality, presenting extraordinary unmet patient need.
The more targeted approach of IAM-C1 offers a more favorable safety profile by reducing dose-limiting toxicities associated with non-CDK2/4 kinases, including CDK6.
KIF18A
KIF18A is a kinesin that helps regulate microtubule dynamics in the cell cycle metaphase. In healthy dividing cells there is little reliance on KIF18A, whereas chromosomally unstable tumor cells are critically dependent on it. Therefore inhibition of this motor protein has potential for strong anti-proliferative effect across a wide range of solid tumors, while sparing healthy dividing cells such as bone-marrow and epithelial cells.
We have designed a novel lead series of allosteric inhibitors for KIF18A, exhibiting single-digit nanomolar potency in both biochemical inhibition assays as well as cell growth inhibition for suitably chosen tumor-derived cell lines. Moreover the series has excellent selectivity with respect to cellular and organelle models of toxicity. Using our powerful AI-driven platform we have designed a series of compounds with good drug-like and ADME properties, clean DDI profiles, and excellent pharmacokinetics.
A number of lead compounds induce potent tumor growth inhibition (TGI) in preclinical models, and in vivo pharmacodynamics studies further demonstrate that observed TGI activity is driven by the expected mechanism of mitotic arrest.
GPCR target
Undisclosed
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