Molecular Bidents with Two Electrophilic Warheads as a New Pharmacological Modality

A systematic strategy
to develop dual-warhead inhibitors
is introduced
to circumvent the limitations of conventional covalent inhibitors
such as vulnerability to mutations of the corresponding nucleophilic
residue. Currently, all FDA-approved covalent small molecules feature
one electrophile, leaving open a facile route to acquired resistance.
We conducted a systematic analysis of human proteins in the protein
data bank to reveal ∼400 unique targets amendable to dual covalent
inhibitors, which we term “molecular bidents”. We demonstrated
this strategy by targeting two kinases: MKK7 and EGFR. The designed
compounds, ZNL-8162 and ZNL-0056, are ATP-competitive inhibitors that
form two covalent bonds with cysteines and retain potency against
single cysteine mutants. Therefore, molecular bidents represent a
new pharmacological modality with the potential for improved selectivity,
potency, and drug resistance profile.

本研究提出了一种开发双弹头抑制剂（dual-warhead inhibitors）的系统性策略，以规避传统共价抑制剂（covalent inhibitors）的局限性：此类抑制剂易受对应亲核残基（nucleophilic residue）突变的影响。目前，所有获美国食品药品监督管理局（Food and Drug Administration, FDA）批准的共价小分子药物均仅含一个亲电基团，这为获得性耐药的产生留下了便捷路径。我们对蛋白质数据库（Protein Data Bank, PDB）中的人类蛋白质开展了系统性分析，鉴定出约400个可适配双共价抑制剂的独特靶点，并将其命名为“分子双齿配体（molecular bidents）”。我们通过靶向两种激酶——丝裂原活化蛋白激酶激酶7（MKK7）与表皮生长因子受体（EGFR），验证了该策略的可行性。所设计的化合物ZNL-8162与ZNL-0056均为ATP竞争性抑制剂，可与半胱氨酸形成两个共价键，且对单半胱氨酸突变体仍保留抑制活性。因此，分子双齿配体代表了一种全新的药理学范式，有望实现更高的选择性、抑制活性以及更优异的耐药谱。